Antiviral Therapy 2015; 20:397–405 (doi: 10.3851/IMP2920)
Original article Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects Matt S Anderson1*, Jocelyn Gilmartin1, Caroline Cilissen2, Inge De Lepeleire2, Luc Van Bortel3, Marissa F Dockendorf1, Ernestina Tetteh1, June K Ancona1, Rachael Liu1, Ying Guo1, John A Wagner1, Joan R Butterton1 Merck & Co., Inc., Kenilworth, NJ, USA Merck, Sharp & Dohme (Europe) Inc., Brussels, Belgium 3 University Hospital Ghent, Drug Research Unit, Ghent, Belgium 1 2
*Corresponding author e-mail: [email protected]
Background: Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug–drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. Methods: The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6–1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30–750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). Results: The maximum plasma concentration (Cmax) of doravirine was achieved within 1–5 h with an apparent terminal half-life of 12–21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7
days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1–1.5 in the area under the plasma concentration–time curve during the dosing interval (AUC0–24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0–∞) and C24 h with no change in Cmax. Midazolam AUC0–∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. Conclusions: Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.
Introduction Doravirine (also known as MK-1439) is an allosteric inhibitor of HIV-1 reverse transcriptase (RT) that binds to a hydrophobic pocket in the p66 subunit of the p66/ p51 heterodimer near the polymerase active site, the classic binding pocket for non-nucleoside RT inhibitors (NNRTIs). Five NNRTIs are currently available for clinical use: efavirenz, nevirapine, delavirdine, etravirine and rilpivirine. However, the genetic barrier to resistance development in this class is relatively low, and ©2015 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-14-OA-3365_Anderson.indd 397
viral strains resistant to current NNRTIs can limit their clinical utility [1]. In biochemical assays, doravirine displays a 95% inhibitory concentration (IC95)of 19 nM in the inhibition of the RNA-dependent DNA polymerization catalysed by HIV-1 RT and also displays low nanomolar potencies versus the most prevalent NNRTI resistant mutants (for example, mutant viruses K103N: IC95 42 nM; Y181C: IC95 25 nM; K103N/Y181C: IC95 54 nM). Doravirine exhibits a superior resistance profile 397
26/06/2015 16:23:48
MS Anderson et al.
compared with the most widely used NNRTI, efavirenz, when tested against a broader array of clinically relevant NNRTI-resistant viruses in antiviral assays [2]. In addition, non-B subtype viruses are also highly susceptible to doravirine with 50% effective concentration (EC50) similar to that obtained with B subtype viruses. Doravirine displays moderate (approximately 75%) binding to human plasma proteins. In vitro and clinical studies have demonstrated that doravirine is primarily cleared by CYP3A4 metabolism with a small component (approximately 6% of administered dose) of elimination via renal excretion. Doravirine has low potential to cause drug interactions; it is not an inhibitor of major CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) and has minimal potential to induce CYP3A4 activity. In vitro evaluation indicated that doravirine is a substrate of human P-glycoprotein but not of OATP1B1. Clinically significant drug interactions via inhibition of major human efflux and uptake transporters are not anticipated based on in vitro data. This report describes the results of two Phase I studies conducted in healthy subjects to investigate the single- and multiple-dose pharmacokinetics and safety of doravirine. The effect of food on the single-dose pharmacokinetics of doravirine, and the influence of steadystate doravirine on the single-dose pharmacokinetics of the CYP3A substrate midazolam, were also evaluated.
Methods Study 1 (MK-1439 Protocol 001; EudraCT 2010024245-70) was a double-blind, randomized, placebocontrolled study in healthy male subjects between 18 and 50 years of age (inclusive) conducted from 17 March 2011 to 30 August 2011. Part I explored rising single doses of doravirine ranging from 6 to 450 mg in two alternating panels of eight subjects each (Table 1). Subjects were randomly assigned to receive doravirine (n=6) or matching placebo (n=2) in up to five treatment periods, with 7–14 days washout between periods. All doses were administered after fasting, with the exception of 50 mg, which was given after fasting in one period and after a high-fat breakfast (500 calories in fat, 220 calories in carbohydrates and 24 calories in protein) in another period to evaluate the effect of food. Part II was an exploration of multiple doses of doravirine in four serial, rising multiple-dose panels (Table 2). Subjects were randomly assigned to receive doravirine (n=6) 30, 60 or 240 mg, respectively, or matching placebo (n=2) once daily for 10 days. To evaluate the effect of doravirine administration on CYP3A4 activity, ten subjects received doravirine 120 mg (n=8) or matching placebo (n=2) once daily for 14 days, plus a single 2-mg dose of midazolam HCl syrup (2 mg/ml) on days -1 and 13. 398
AVT-14-OA-3365_Anderson.indd 398
Study 2 (MK-1439 Protocol 006; EudraCT 2011004260-30) was a double-blind, randomized, placebocontrolled study in healthy male subjects between 18 and 50 years of age conducted from 8 November 2011 to 1 June 2012, to evaluate higher doses of doravirine than those explored in study 1. Two panels of eight subjects each were randomly assigned to receive doravirine or matching placebo (in a 3:1 ratio) in up to three treatment periods (Table 3). In periods 1 and 2, subjects received a single oral dose of doravirine (600 to 1,200 mg) or matching placebo, respectively. In period 3, subjects received doravirine (450 or 750 mg) or matching placebo once daily for 10 days. Each subject had a 7-day washout period between study drug administration in period 1 and 2, and between period 2 and the first dose of study drug in period 3. Both studies were conducted at University Hospital Ghent, Drug Research Unit, Ghent, Belgium and followed applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. The study protocols were approved by the Ethical Review Committee of Table 1. Doravirine rising single-dose treatment groups (study 1, part I) Panel
Period 1 Period 2
Period 3
Period 4
A B
6 mg 12 mg
100 mg 150 mg
300 mg 450 mg 50 mg with food 600 mg
25 mg 50 mg
Period 5
Eight subjects per panel. In each period, six subjects received doravirine and two received matching placebo. The 600 mg dose (panel B, period 5) was not administered.
Table 2. Doravirine rising multiple-dose treatment groups (study 1, part II) Panel
Dose assignment
Ca Da Eb Fa
30 mg once daily ×10 days 60 mg once daily ×10 days 120 mg once daily ×14 days (days 1–14) and 2.0 mg midazolam HCL syrup as single doses on days -1 and 13 240 mg once daily ×10 days
a Eight subjects received doravirine (n=6) or matching placebo (n=2). bTen subjects received doravirine (n=8) or matching placebo (n=2).
Table 3. Doravirine higher dose treatment groups (study 2) Panel
Period 1
Period 2
Period 3
A B
600 mg 1,000 mg
800 mg 1,200 mg
500 mg once daily ×10 days 750 mg once daily ×10 days
Eight subjects per panel. In each period, six subjects received doravirine and two received matching placebo. ©2015 International Medical Press
26/06/2015 16:23:48
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
University Hospital Ghent, and all subjects provided written informed consent before any study procedures were performed. To be eligible for the study, subjects were to be non-smokers in good health based on medical history, physical examination, vital sign measurements and laboratory safety tests, with a body mass index ≤35 kg/m2, estimated creatinine clearance >80 ml/min and no clinically significant abnormalities on electrocardiogram (ECG). The use of any medication (other than acetaminophen) from approximately 2 weeks (or 5 half-lives) before the initial dose of study drug until the post-study visit required approval of the investigator and the sponsor. Study drugs were provided as tablets at potencies of 1 mg, 10 mg and 100 mg of doravirine or placebo for all study panels. Blood samples were obtained at multiple time points to assess doravirine single-dose and multiple-dose pharmacokinetics and to determine the pharmacokinetic parameters of midazolam before and after multiple doses of doravirine. Safety was assessed by repeated clinical evaluation of adverse events and inspection of other study parameters including vital signs, medical history, physical examination, 12-lead ECG and standard laboratory safety tests (haematology, chemistry and urinalysis).
Analytical and pharmacokinetic methods Plasma samples were analysed for doravirine concentration using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay with a lower limit of quantitation of 2.3 nM. Plasma samples were analysed by inVentiv Health Clinique (Quebec City, QC, Canada) for midazolam concentrations using liquid–liquid extraction and a validated LC-MS/MS assay (lower limit of detection 20 pg/ml; calibration range 20 to 20,000 pg/ml). The maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and trough plasma concentration (C24 h) were obtained directly from plasma concentration–time data. The area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC0–∞) and during the dosing interval (AUC0–24 h) were calculated using the linear up/log down trapezoidal method. The apparent terminal half-life was calculated as (ln2)/l, where l is the apparent terminal rate constant, calculated from a semi-log plot of the plasma concentration-versus-time curve. Time to steady state was determined by visual inspection.
Statistical analysis Analysis of the single-dose data used a linear mixedeffects model with fixed effect for treatment and a random effect for subject. Analysis of the multiple-dose data used a linear mixed-effects model with dose, day (day 1 and the last day of dosing) and dose-by-day interaction Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 399
as fixed effects, and subject-within-dose as a random effect. Natural–log transformation was performed for C24 h, Cmax, AUC0–∞ and AUC0–24 h before analysis.
Results Subjects Fifty male subjects (46 White, 3 Black, 1 Asian) between 20 and 49 years of age (mean 30.0 years) enrolled in study 1; weight ranged from 63.0 to 105.6 kg (mean 79.5 kg). None of the subjects required a concomitant medication during the study. Forty-eight subjects completed the study. One subject (assigned to doravirine 120 mg once daily) discontinued due to a laboratory adverse event (details provided in Safety) and one (assigned to placebo) discontinued from the study for personal reasons. Sixteen male subjects (all white) between 23 and 50 years of age (mean, 38.4 years) enrolled in study 2; weight ranged from 67.4 to 120.8 kg (mean 85.5 kg). Concomitant medications used during the study were acetaminophen for one day in three subjects, and acetaminophen and ibuprofen for one day and amoxicillin/ clavulanic acid for 6 days in one subject. Fifteen subjects completed the study. One subject (assigned to doravirine 750 mg once daily) discontinued due to a serious adverse event (details provided in Safety).
Pharmacokinetics Single doses of doravirine given in the fasted state were rapidly absorbed, with median Tmax values ranging from 1.0 to 4.0 h post-dose (Table 4). Doravirine plasma concentrations declined in a single exponential phase (Figure 1), with an apparent terminal half-life of 12 to 19 h. Doravirine AUC0–∞, AUC0–24 h, Cmax and C24 h values increased in a slightly less than dose-proportional manner (Table 4). When doravirine 50 mg was administered with a high-fat meal, the median Tmax was 5.0 h, AUC0–∞ and C24 h increased slightly (fed/fasted geometric mean ratios [GMRs] and 90% CIs: 1.33 [1.12, 1.57] and 1.56 [1.28, 1.91], respectively), and Cmax remained unchanged (GMR [90% CI]: 0.95 [0.78, 1.16]). Over a 24-h period, 6.29% of a single 50-mg dose (in the fasted state) was excreted unchanged in the urine and the mean observed renal clearance was 9.43 ml/min. Consistent with single-dose results, multiple-dose data indicate that doravirine is rapidly absorbed (Tables 5 and 6). The median Tmax values on days 1 and 10 (or 1 and 14 for the 120-mg dose) ranged from 1.0 to 4.0 h. After 10–14 days of once-daily dosing, doravirine plasma concentrations declined in a single exponential phase (Figure 2), with an apparent terminal half-life of 13 to 21 h. Most subjects achieved steady state by day 7. Steady state AUC0–24 h and Cmax increased in a slightly less than dose-proportional manner, as was observed during single-dose administration. At steady 399
26/06/2015 16:23:48
MS Anderson et al.
Table 4. Summary statistics of pharmacokinetic parameters of doravirine after single oral doses in healthy males Apparent Dose, mg AUC0–∞, µM•ha AUC0–24 h, µM•ha Cmax, nMa C24 h, nMa Tmax, hb terminal t1/2, hc Study 1 6 12 25 50 50d 100 150 300 450 Study 2 600 800 1,000 1,200
2.88 (2.36, 3.51) 4.80 (3.94, 5.86) 11.21 (9.20, 13.66) 17.66 (14.47, 21.56) 23.48 (19.23, 28.67) 38.32 (31.46, 46.66) 50.16 (41.14, 61.15) 92.54 (75.92, 112.80) 126.58 (103.93, 154.16)
2.03 (1.71, 2.40) 3.62 (3.05, 4.29) 7.02 (5.92, 8.32) 12.68 (10.68, 15.04) 15.88 (13.39, 18.84) 22.84 (19.28, 27.06) 34.09 (28.76, 40.41) 58.87 (49.66, 69.78) 82.41 (69.56, 97.62)
156.10 (126.79, 192.18) 294.70 (239.13, 363.19) 461.27 (374.33, 568.41) 1,067.35 (864.84, 1,317.27) 1,017.43 (824.40, 1,255.67) 1,713.17 (1,391.54, 2,109.15) 2,653.72 (2,153.30, 3,270.44) 3,821.27 (3,101.00, 4,708.85) 6,012.15 (4,883.42, 7,401.78)
43.95 1.00 (1.00, 4.00) (35.26, 54.79) 71.50 1.00 (1.00, 3.00) (57.30, 89.23) 193.71 5.00 (1.00, 6.00) (155.25, 241.69) 269.52 1.00 (1.00, 4.00) (215.63, 336.86) 421.67 5.00 (3.00, 6.00) (337.37, 527.03) 593.43 1.50 (1.00, 5.00) (476.08, 739.71) 758.88 1.50 (1.00, 4.00) (608.14, 946.99) 1,490.08 3.50 (2.00, 5.00) (1,194.25, 1,859.21) 2,068.88 2.00 (1.00, 5.00) (1,659.77, 2,578.84)
11.68 (10.0)
145.61 (121.66, 174.26) 179.14 (149.68, 214.39) 215.93 (180.42, 258.42) 246.12 (205.65, 294.56)
100.91 (86.49, 117.75) 117.96 (101.09, 137.63) 137.73 (118.04, 160.70) 152.39 (130.60, 177.81)
7,416.43 (6,175.06, 8,907.35) 8,179.25 (6,810.20, 9,823.53) 10,085.62 (8,397.47, 12,113.12) 10,788.58 (8,982.78, 12,957.41)
2,243.93 (1,833.50, 2,746.23) 2,572.98 (2,102.36, 3,148.93) 3,199.65 (2,614.42, 3,915.89) 3,635.73 (2,970.73, 4,449.58)
2.50 (0.50, 4.00)
13.58 (14.1)
4.00 (2.00, 5.00)
16.45 (27.0)
2.00 (0.50, 5.00)
15.42 (11.0)
3.00 (1.00, 5.00)
18.88 (34.2)
11.67 (15.7) 15.67 (20.4) 13.29 (10.6) 13.07 (12.0) 15.26 (44.0) 13.84 (27.6) 15.62 (27.1) 14.80 (34.5)
Back-transformed least-squares mean and 95% CI from linear mixed-effects model performed on natural log-transformed values. bMedian (min, max). cGeometric mean (geometric mean percent coefficient of variation). dAfter a high-fat meal; other doses were given in the fasted state. AUC0–∞, area under the plasma concentration–time curve from time zero to infinity; AUC0–24 h, area under the plasma concentration–time curve during the dosing interval; Cmax, maximum plasma concentration; C24 h, trough plasma concentration; Tmax, time to maximum plasma concentration; t1/2, half-life. a
state, the mean AUC0–24 h, Cmax and C24 h accumulation ratios, expressed as the day 10/day 1 GMRs (or day 14/ day 1 GMRs for the 120-mg dose) were 1.1 to 1.5, consistent with predictions from single-dose data. However, some variability in individual accumulation ratios was noted. The observed AUC0–24 h accumulation ratios at each dose correspond to a mean effective accumulation half-life of approximately 9 to 14 h. The overall shape of the single-dose midazolam concentration–time profile was similar whether administered alone or with doravirine 120 mg at steady state (Additional file 1). Midazolam exposure (AUC0–∞) was slightly decreased in the presence of doravirine (GMR [90% CI] 0.82 [0.70, 0.97]), while Cmax was unchanged (GMR [90% CI] 1.02 [0.81, 1.28]; Table 7).
Safety Study 1: 34 subjects reported a total of 98 non-serious clinical adverse events. Of the 37 adverse events considered possibly or probably related to study drug, 26 400
AVT-14-OA-3365_Anderson.indd 400
occurred in subjects who received doravirine: headache (12), back pain (2), dizziness (2), somnolence (2), abdominal discomfort (1) or pain (1), dysgeusia (1), fatigue (1), feeling hot (1), involuntary leg muscle contractions (1), loose stools (1) and neck stiffness (1). Doravirine (120 mg once daily) was discontinued in one subject due to slightly elevated aspartate transaminase (AST; 1.6× upper limit of normal [ULN]) with normal alanine aminotransferase (ALT; 0.71×ULN) and very high creatine kinase (CK; 15.0×ULN) on day 5. These values peaked on day 7 (AST 2.8×ULN, ALT 1.1×ULN, CK 30.4×ULN) and declined to within normal range over the next 7 days. The subject did not report any clinical symptoms at any time during this period. This event was judged to be related to muscle damage due to patient-reported heavy physical activity, possibly aggravated by the concomitant use of doravirine. A second subject, who received placebo to match 30 mg doravirine, withdrew consent for personal reasons following the day 4 dose ©2015 International Medical Press
26/06/2015 16:23:48
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
Figure 1. Mean doravirine plasma concentration versus time profile following single doses of doravirine, 6 to 1,200 mg, in healthy male subjects
100,000 10,000 12,000
Mean doravirine plasma concentration, nM
1,000 10,000
100 10
8,000
1 6,000
0
12
24
36
48
60
72
84
96
108 120
4,000
2,000
0 0
12
24
36
48
60
6 mg 12 mg 25 mg 50 mg 100 mg 150 mg 50 mg with food 300 mg 450 mg 600 mg 800 mg 1,000 mg 1,200 mg
72
Time, h
Linear scale, first 72 h post-dose. Inset: semi-log scale.
Table 5. Summary statistics of pharmacokinetic parameters of doravirine after once-daily oral doses in fasted healthy males (study 1) Apparent Dose, mg Day n AUC0–24 h, µM•ha Cmax, nMa C24 h, nMa Tmax, hb terminal t1/2, hc 30
GMRd 60 GMRd 120 GMRd 240 GMRd
1 6 10 6 10/1 6 1 6 10 6 10/1 6 1 8 14 7e 14/1 7 1 6 10 6 10/1 6
8.42 (6.49, 10.92) 11.46 (8.84, 14.87) 1.36 (1.19, 1.56) 14.10 (10.87, 18.28) 17.33 (13.36, 22.48) 1.23 (1.07, 1.41) 27.31 (21.81, 34.21) 36.79 (29.22, 46.32) 1.35 (1.19, 1.53) 43.75 (33.73, 56.75) 60.59 (46.72, 78.58) 1.38 (1.21, 1.59)
671.52 (515.32, 875.08) 795.73 (610.63, 1,036.93) 1.18 (0.99, 1.42) 1,023.60 (785.50, 1,333.89) 1,303.22 (1,000.07, 1,698.26) 1.27 (1.07, 1.52) 1,920.63 (1,527.08, 2,415.61) 2,517.95 (1,985.69, 3,192.88) 1.31 (1.11, 1.54) 3,243.23 (2,488.80, 4,226.35) 4,474.70 (3,433.81, 5,831.12) 1.38 (1.16, 1.65)
177.02 (125.16, 250.37) 245.71 (173.73, 347.52) 1.39 (1.17, 1.64) 335.50 (237.22, 474.52) 384.66 (271.97, 544.05) 1.15 (0.97, 1.36) 670.92 (496.92, 905.84) 874.72 (644.19, 1,187.73) 1.30 (1.12, 1.52) 1,062.36 (751.13, 1,502.54) 1,340.65 (947.90, 1,896.14) 1.26 (1.07, 1.49)
1.00 (1.00, 5.00) 3.50 (1.00, 5.00) – 3.00 (1.00, 4.02) 2.00 (1.00, 4.00) – 2.00 (1.00, 4.00) 4.00 (1.00, 5.00) – 1.50 (1.00, 5.00) 3.00 (1.00, 5.00) –
NA 13.63 (11.3) – NA 12.59 (18.3) – NA 14.99 (22.9) – NA 13.35 (15.9) –
Back-transformed least-squares mean and 95% CI from linear mixed-effects model performed on natural log-transformed values. bMedian (min, max). cGeometric mean (geometric mean percent coefficient of variation). dDay 10 or 14/day1: back-transformed geometric mean ratio (GMR) and 90% CI from linear mixed-effects model performed on natural log-transformed values. eOne subject was excluded due to insufficient pharmacokinetic sampling. AUC0–24 h, area under the plasma concentration–time curve during the dosing interval; Cmax, maximum plasma concentration; C24 h, trough plasma concentration; NA, not applicable; Tmax, time to maximum plasma concentration; t1/2, half-life. a
Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 401
401
26/06/2015 16:23:48
MS Anderson et al.
Table 6. Summary statistics of pharmacokinetic parameters of doravirine after once-daily oral doses in fasted healthy males (study 2) Apparent Dose, mg Day n AUC0–24 h, µM•ha Cmax, nMa C24 h, nMa Tmax, hb terminal t1/2, hc 450
GMRd 750 GMRd
1 6 10 6 10/1 6 1 6 10 5e 10/1 5e
81.98 (70.21, 95.72) 100.10 (85.74, 116.88) 1.22 (1.13, 1.32) 99.15 (84.92, 115.76) 137.77 (117.59, 161.40) 1.39 (1.28, 1.51)
5,578.49 (4,814.61, 6,463.55) 7,589.78 (6,550.50, 8,793.95) 1.36 (1.15, 1.61) 6,976.13 (6,020.88, 8,082.94) 10,498.37 (8,909.63, 12,370.41) 1.50 (1.26, 1.79)
1,936.40 (1,516.41, 2,472.71) 2,092.18 (1,638.40, 2,671.64) 1.08 (0.95, 1.23) 2,367.85 (1,854.27, 3,023.66) 2,854.57 (2,219.84, 3,670.79) 1.21 (1.04, 1.39)
3.00 (1.00, 4.00) 1.50 (1.00, 4.00) – 3.00 (1.00, 5.00) 1.00 (0.52, 5.00) –
NA 14.67 (30.5) – NA 20.95 (55.1) –
Back-transformed least-squares mean and 95% CI from linear mixed-effects model performed on natural log-transformed values. bMedian (min, max). cGeometric mean (geometric mean percent coefficient of variation). dDay 10/day1: back-transformed geometric mean ratio (GMR) and 90% CI from linear mixed-effects model performed on natural log-transformed values. eOne subject was excluded due to insufficient pharmacokinetic sampling. AUC0–24 h, area under the plasma concentration– time curve during the dosing interval; Cmax, maximum plasma concentration; C24 h, trough plasma concentration; NA, not applicable; Tmax, time to maximum plasma concentration; t1/2, half-life. a
and discontinued from the study. No serious adverse events were reported, and there were no consistent, clinically relevant, treatment-related effects of doravirine on vital signs or ECGs. Study 2: 14 subjects reported a total of 104 nonserious clinical adverse events. Of the 38 adverse events considered possibly related to study drug, 30 occurred in subjects who received doravirine: headache (17), nausea (4), fatigue (2), somnolence (2), stomach discomfort (1), irritability (1), musculoskeletal chest pain (1), neck pain (1) and vomiting (1). All of the non-serious clinical adverse events were mild or moderate in intensity and of limited duration. One serious adverse event of sarcoidosis was reported after administration of 750 mg doravirine once daily for 7 days. This event was determined to be probably not drug related, due to a medical history of multiple preceding upper respiratory infections and a histopathological examination of enlarged mediastinal lymph nodes biopsied during the study that revealed granulomas. The findings supported the investigator’s conclusion that sarcoidosis was likely a pre-existing condition. Overall, no clinically significant trends or signals were observed in laboratory assessments, vital signs or ECGs.
Discussion The safety, tolerability and pharmacokinetics of doravirine were investigated in two single- and multipleascending dose studies that explored a wide range of doses (6 to 1,200 mg) in healthy male subjects. Doravirine was rapidly absorbed after both single-dose and multiple-dose administration, with median Tmax values of 1 to 5 h post-dose. Thereafter, concentrations declined in a single exponential phase, with an apparent terminal half-life of 12 to 21 h. AUC and Cmax values increased in a slightly less than dose-proportional manner after both single- and multiple-dose administration. After multiple days of once-daily dosing, most 402
AVT-14-OA-3365_Anderson.indd 402
subjects achieved steady state by day 7. The observed AUC0–24 h accumulation ratios of 1.2 to 1.4 correspond to a mean effective accumulation half-life of approximately 9 to 14 h. For the NNRTI and protease inhibitor classes of antiretroviral agents, there is a general association of efficacy with doses that achieve trough concentration values exceeding the protein-adjusted IC95 in the HIV spread assay, in which IC95 is defined as the concentration at which replication/reinfection of the virus in a cell culture setting is inhibited by >95% in the presence of 50% normal human serum [3]. These pharmacokinetic/pharmacodynamic relationships have been supported by experiments using an in vitro hollow-fibre bioreactor system where exposure of HIV-infected cells to each inhibitor class can be carefully controlled over time [4]. Using time above trough concentration as the key parameter, population pharmacokinetic modelling for one novel NNRTI has successfully predicted clinical effects on HIV viral load in a Phase Ib proofof-concept study [5]. In the current study, single doses of doravirine, 12 mg and higher, resulted in geometric mean C24 h exceeding the in vitro IC95 in 50% human serum of not only wild-type virus (IC95 19 nM), but also that of several common efavirenz resistance mutations, including the double mutant K103N/Y181C (IC95 54 nM). These trough levels were durably sustained following multiple once-daily dosing. These results were utilized as one factor in dose selection for the subsequent Phase II dose-ranging study in HIVinfected patients [6]. After administration of a single 50-mg dose, only a minimal amount of doravirine was excreted unchanged in the urine (6.3% over a 24-h period), while mean observed renal clearance was low (9.43 ml/min). These results suggest that urinary excretion is not a major route of doravirine elimination. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC0–∞ and C24 h with no change in Cmax. This food effect is unlikely to ©2015 International Medical Press
26/06/2015 16:23:49
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
Figure 2. Mean doravirine plasma concentration versus time profile following once daily oral doses of doravirine, 30 to 750 mg, for 10 or 14 days in healthy male subjects
Mean doravirine plasma concentration, nM
12,000
10,000 30 mg ×10 days 60 mg ×10 days 120 mg ×14 days 240 mg ×10 days 450 mg ×10 days 750 mg ×10 days
8,000
6,000
4,000
2,000
0 0
12
24 3
5
Time, h
7
9
11
13 0
12
24
36
48
Day
60
72
84
96
108
120
84
96
108
120
Time, h
Day 1
Day 10 or 14
Mean doravirine plasma concentration, nM
100,000
10,000
1,000
100
10
1 0
12
24 3
Time, h
5
7
9
11
13 0
Day
Day 1
12
24
36
48
60
72
Time, h Day 10 or 14
Upper plot: linear; lower plot: semi-log.
be clinically meaningful, although continued development will clarify pharmacokinetic/pharmacodynamic relationships. In vitro studies predict that doravirine has low potential to be a perpetrator of drug interactions via CYP metabolism. In the current study, midazolam exposure was decreased by approximately 18% Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 403
in the presence of doravirine, while Cmax remained unchanged with concomitant doravirine administration. As midazolam is a sensitive CYP3A4 substrate, these results support the position that doravirine is not a significant inhibitor of CYP3A4 metabolism and also suggest that doravirine may be a weak inducer of CYP3A4. 403
26/06/2015 16:23:49
MS Anderson et al.
Table 7. Statistical comparison of pharmacokinetic parameters after midazolam 2 mg alone or with multiple oral doses of doravirine 120 mg in healthy males Parameter
Midazolam (n=8)a
Doravirine + midazolam (n=7)a,b
(Doravirine + midazolam)/midazolamc
AUC0–∞, ng/ml•hd Cmax, ng/mld Tmax, he Apparent terminal t1/2, hf
32.87 (19.40, 55.68) 9.97 (6.83, 14.55) 1.0 (0.50–1.50) 3.81 (62.2)
26.98 (15.90, 45.78) 10.14 (6.90, 14.91) 0.5 (0.33–0.50) 3.41 (65.6)
0.82 (0.70, 0.97) 1.02 (0.81, 1.28) – –
a Values are geometric mean (GM [95% CI]) unless otherwise indicated. bOne subject had missing pharmacokinetic data when doravirine and midazolam were coadministered. cValues are geometric mean ratio (GMR [90% CI]). dBack-transformed least squares mean and CI from mixed effects model performed on natural logtransformed values. eValues are median (range). fValues are GM (geometric mean percent coefficient of variation [GCV]). GCV is calculated in the natural log-scale with the equation: 100× the square root (exp(s2)-1), where s2 is the observed variance on the natural log-scale. AUC0–∞, area under the plasma concentration–time curve from time zero to infinity; Cmax, maximum plasma concentration; Tmax, time to maximum plasma concentration; t1/2, half-life.
In these two studies of healthy male subjects, doravirine was generally well tolerated when given orally as single doses ranging from 6 to 1,200 mg and as multiple doses ranging from 30 to 750 mg once daily for 10–14 days. One serious adverse event (sarcoidosis) was reported in a subject receiving doravirine 750 mg once daily, but was judged probably not related to doravirine. All of the non-serious clinical adverse events were mild or moderate in intensity and of limited duration. No clinically significant trends or signals were observed in clinical laboratory assessments, vital signs or ECGs. In summary, the results of these studies indicate that doravirine is generally well tolerated and exhibits a pharmacokinetic profile supportive of once-daily dosing. Trough concentrations predictive of virological suppression of wild-type and of common NNRTI-resistant strains were achieved with single doses as low as 12 mg, and were maintained over 10 days of once-daily dosing. At steady state, doravirine 120 mg did not have a significant effect on midazolam exposure, consistent with in vitro studies suggesting that doravirine has limited potential for drug interactions mediated by CYP3A4. These results support the further clinical development of doravirine as a once-daily NNRTI. Based on the week 24 results of the Phase II, dose-finding study of doravirine 25, 50, 100 and 200 mg once daily in HIVinfected patients, the 100-mg dose of doravirine has been selected for further development [6].
Inc. The study was designed, managed and analysed by the sponsor in conjunction with external investigators. Authors had access to all study data upon request. All authors approved the final version of the manuscript for submission. The manuscript was also reviewed by the sponsor. The opinions expressed in the manuscript represent the collective views of the authors and do not necessarily reflect the official position of Merck or the institutions affiliated with the academic authors. LVB has received grants for clinical trial conduct from Merck, Janssen, GSK, Actogenix, Daiichi-Sankyo, Menarini and Yakult; speaker fees from Novartis, Janssen, Recordati, and AIM; and conference support from Servier and Daiichi-Sankyo. The remaining authors are current or former employees of Merck & Co., Inc. and may own stock and/or stock options in the company.
Additional file Additional file 1: Mean plasma concentration profiles of midazolam alone and coadministered with doravirine 120 mg once daily in healthy male subjects can be found at http://www.intmedpress.com/uploads/ documents/3365_Anderson_Addfile1.pdf
References 1.
Acknowledgements We thank the subjects who participated in this study, the clinical research unit staff, and Karyn Davis and Kim Strohmaier (both of Merck & Co., Inc., Kenilworth, NJ, USA) for medical writing assistance.
Disclosure statement This study was sponsored and funded by Merck, Sharp & Dohme Corp., a subsidiary of Merck & Co., 404
AVT-14-OA-3365_Anderson.indd 404
2.
3. 4.
de Béthune MP. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009). Antiviral Res 2010; 85:75–90. Lai MT. Antiviral activity and in vitro mutation development pathways of MK-1439: a novel non-nucleoside reverse transcriptase inhibitor (NNRTI). Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC). 9–12 September 2012, San Francisco, CA, USA. Abstract H551. Vacca JP, Dorsey BD, Schleif WA, et al. L-735,524: an orally bioavailable human immuno-deficiency virus type 1 protease inhibitor. Proc Natl Acad Sci U S A 1994; 91:4096–4100. Bilello JA, Bauer G, Dudley MN, Cole GA, Drusano GL. Effect of 2′,3′-didehydro-3′-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies. Antimicrob Agents Chemother 1994; 38:1386–1391. ©2015 International Medical Press
26/06/2015 16:23:49
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
5.
Drusano GL, Moore KH, Kleim JP, Prince W, Bye A. Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation. Antimicrob Agents Chemother 2002; 46:913–916.
6.
Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety & antiviral effect of MK-1439, a novel NNRTI, (+TDF/ FTC) in ART-naive HIV infected patients. Conference on Retroviruses and Opportunistic Infections (CROI). 3–6 March 2014, Boston, MA, USA. Abstract 92LB.
Accepted 31 October 2014; published online 3 December 2014
Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 405
405
26/06/2015 16:23:49
Original article Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects Matt S Anderson1*, Jocelyn Gilmartin1, Caroline Cilissen2, Inge De Lepeleire2, Luc Van Bortel3, Marissa F Dockendorf1, Ernestina Tetteh1, June K Ancona1, Rachael Liu1, Ying Guo1, John A Wagner1, Joan R Butterton1 Merck & Co., Inc., Kenilworth, NJ, USA Merck, Sharp & Dohme (Europe) Inc., Brussels, Belgium 3 University Hospital Ghent, Drug Research Unit, Ghent, Belgium 1 2
*Corresponding author e-mail: [email protected]
Background: Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug–drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. Methods: The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6–1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30–750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). Results: The maximum plasma concentration (Cmax) of doravirine was achieved within 1–5 h with an apparent terminal half-life of 12–21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7
days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1–1.5 in the area under the plasma concentration–time curve during the dosing interval (AUC0–24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0–∞) and C24 h with no change in Cmax. Midazolam AUC0–∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. Conclusions: Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.
Introduction Doravirine (also known as MK-1439) is an allosteric inhibitor of HIV-1 reverse transcriptase (RT) that binds to a hydrophobic pocket in the p66 subunit of the p66/ p51 heterodimer near the polymerase active site, the classic binding pocket for non-nucleoside RT inhibitors (NNRTIs). Five NNRTIs are currently available for clinical use: efavirenz, nevirapine, delavirdine, etravirine and rilpivirine. However, the genetic barrier to resistance development in this class is relatively low, and ©2015 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-14-OA-3365_Anderson.indd 397
viral strains resistant to current NNRTIs can limit their clinical utility [1]. In biochemical assays, doravirine displays a 95% inhibitory concentration (IC95)of 19 nM in the inhibition of the RNA-dependent DNA polymerization catalysed by HIV-1 RT and also displays low nanomolar potencies versus the most prevalent NNRTI resistant mutants (for example, mutant viruses K103N: IC95 42 nM; Y181C: IC95 25 nM; K103N/Y181C: IC95 54 nM). Doravirine exhibits a superior resistance profile 397
26/06/2015 16:23:48
MS Anderson et al.
compared with the most widely used NNRTI, efavirenz, when tested against a broader array of clinically relevant NNRTI-resistant viruses in antiviral assays [2]. In addition, non-B subtype viruses are also highly susceptible to doravirine with 50% effective concentration (EC50) similar to that obtained with B subtype viruses. Doravirine displays moderate (approximately 75%) binding to human plasma proteins. In vitro and clinical studies have demonstrated that doravirine is primarily cleared by CYP3A4 metabolism with a small component (approximately 6% of administered dose) of elimination via renal excretion. Doravirine has low potential to cause drug interactions; it is not an inhibitor of major CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) and has minimal potential to induce CYP3A4 activity. In vitro evaluation indicated that doravirine is a substrate of human P-glycoprotein but not of OATP1B1. Clinically significant drug interactions via inhibition of major human efflux and uptake transporters are not anticipated based on in vitro data. This report describes the results of two Phase I studies conducted in healthy subjects to investigate the single- and multiple-dose pharmacokinetics and safety of doravirine. The effect of food on the single-dose pharmacokinetics of doravirine, and the influence of steadystate doravirine on the single-dose pharmacokinetics of the CYP3A substrate midazolam, were also evaluated.
Methods Study 1 (MK-1439 Protocol 001; EudraCT 2010024245-70) was a double-blind, randomized, placebocontrolled study in healthy male subjects between 18 and 50 years of age (inclusive) conducted from 17 March 2011 to 30 August 2011. Part I explored rising single doses of doravirine ranging from 6 to 450 mg in two alternating panels of eight subjects each (Table 1). Subjects were randomly assigned to receive doravirine (n=6) or matching placebo (n=2) in up to five treatment periods, with 7–14 days washout between periods. All doses were administered after fasting, with the exception of 50 mg, which was given after fasting in one period and after a high-fat breakfast (500 calories in fat, 220 calories in carbohydrates and 24 calories in protein) in another period to evaluate the effect of food. Part II was an exploration of multiple doses of doravirine in four serial, rising multiple-dose panels (Table 2). Subjects were randomly assigned to receive doravirine (n=6) 30, 60 or 240 mg, respectively, or matching placebo (n=2) once daily for 10 days. To evaluate the effect of doravirine administration on CYP3A4 activity, ten subjects received doravirine 120 mg (n=8) or matching placebo (n=2) once daily for 14 days, plus a single 2-mg dose of midazolam HCl syrup (2 mg/ml) on days -1 and 13. 398
AVT-14-OA-3365_Anderson.indd 398
Study 2 (MK-1439 Protocol 006; EudraCT 2011004260-30) was a double-blind, randomized, placebocontrolled study in healthy male subjects between 18 and 50 years of age conducted from 8 November 2011 to 1 June 2012, to evaluate higher doses of doravirine than those explored in study 1. Two panels of eight subjects each were randomly assigned to receive doravirine or matching placebo (in a 3:1 ratio) in up to three treatment periods (Table 3). In periods 1 and 2, subjects received a single oral dose of doravirine (600 to 1,200 mg) or matching placebo, respectively. In period 3, subjects received doravirine (450 or 750 mg) or matching placebo once daily for 10 days. Each subject had a 7-day washout period between study drug administration in period 1 and 2, and between period 2 and the first dose of study drug in period 3. Both studies were conducted at University Hospital Ghent, Drug Research Unit, Ghent, Belgium and followed applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. The study protocols were approved by the Ethical Review Committee of Table 1. Doravirine rising single-dose treatment groups (study 1, part I) Panel
Period 1 Period 2
Period 3
Period 4
A B
6 mg 12 mg
100 mg 150 mg
300 mg 450 mg 50 mg with food 600 mg
25 mg 50 mg
Period 5
Eight subjects per panel. In each period, six subjects received doravirine and two received matching placebo. The 600 mg dose (panel B, period 5) was not administered.
Table 2. Doravirine rising multiple-dose treatment groups (study 1, part II) Panel
Dose assignment
Ca Da Eb Fa
30 mg once daily ×10 days 60 mg once daily ×10 days 120 mg once daily ×14 days (days 1–14) and 2.0 mg midazolam HCL syrup as single doses on days -1 and 13 240 mg once daily ×10 days
a Eight subjects received doravirine (n=6) or matching placebo (n=2). bTen subjects received doravirine (n=8) or matching placebo (n=2).
Table 3. Doravirine higher dose treatment groups (study 2) Panel
Period 1
Period 2
Period 3
A B
600 mg 1,000 mg
800 mg 1,200 mg
500 mg once daily ×10 days 750 mg once daily ×10 days
Eight subjects per panel. In each period, six subjects received doravirine and two received matching placebo. ©2015 International Medical Press
26/06/2015 16:23:48
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
University Hospital Ghent, and all subjects provided written informed consent before any study procedures were performed. To be eligible for the study, subjects were to be non-smokers in good health based on medical history, physical examination, vital sign measurements and laboratory safety tests, with a body mass index ≤35 kg/m2, estimated creatinine clearance >80 ml/min and no clinically significant abnormalities on electrocardiogram (ECG). The use of any medication (other than acetaminophen) from approximately 2 weeks (or 5 half-lives) before the initial dose of study drug until the post-study visit required approval of the investigator and the sponsor. Study drugs were provided as tablets at potencies of 1 mg, 10 mg and 100 mg of doravirine or placebo for all study panels. Blood samples were obtained at multiple time points to assess doravirine single-dose and multiple-dose pharmacokinetics and to determine the pharmacokinetic parameters of midazolam before and after multiple doses of doravirine. Safety was assessed by repeated clinical evaluation of adverse events and inspection of other study parameters including vital signs, medical history, physical examination, 12-lead ECG and standard laboratory safety tests (haematology, chemistry and urinalysis).
Analytical and pharmacokinetic methods Plasma samples were analysed for doravirine concentration using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay with a lower limit of quantitation of 2.3 nM. Plasma samples were analysed by inVentiv Health Clinique (Quebec City, QC, Canada) for midazolam concentrations using liquid–liquid extraction and a validated LC-MS/MS assay (lower limit of detection 20 pg/ml; calibration range 20 to 20,000 pg/ml). The maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and trough plasma concentration (C24 h) were obtained directly from plasma concentration–time data. The area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC0–∞) and during the dosing interval (AUC0–24 h) were calculated using the linear up/log down trapezoidal method. The apparent terminal half-life was calculated as (ln2)/l, where l is the apparent terminal rate constant, calculated from a semi-log plot of the plasma concentration-versus-time curve. Time to steady state was determined by visual inspection.
Statistical analysis Analysis of the single-dose data used a linear mixedeffects model with fixed effect for treatment and a random effect for subject. Analysis of the multiple-dose data used a linear mixed-effects model with dose, day (day 1 and the last day of dosing) and dose-by-day interaction Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 399
as fixed effects, and subject-within-dose as a random effect. Natural–log transformation was performed for C24 h, Cmax, AUC0–∞ and AUC0–24 h before analysis.
Results Subjects Fifty male subjects (46 White, 3 Black, 1 Asian) between 20 and 49 years of age (mean 30.0 years) enrolled in study 1; weight ranged from 63.0 to 105.6 kg (mean 79.5 kg). None of the subjects required a concomitant medication during the study. Forty-eight subjects completed the study. One subject (assigned to doravirine 120 mg once daily) discontinued due to a laboratory adverse event (details provided in Safety) and one (assigned to placebo) discontinued from the study for personal reasons. Sixteen male subjects (all white) between 23 and 50 years of age (mean, 38.4 years) enrolled in study 2; weight ranged from 67.4 to 120.8 kg (mean 85.5 kg). Concomitant medications used during the study were acetaminophen for one day in three subjects, and acetaminophen and ibuprofen for one day and amoxicillin/ clavulanic acid for 6 days in one subject. Fifteen subjects completed the study. One subject (assigned to doravirine 750 mg once daily) discontinued due to a serious adverse event (details provided in Safety).
Pharmacokinetics Single doses of doravirine given in the fasted state were rapidly absorbed, with median Tmax values ranging from 1.0 to 4.0 h post-dose (Table 4). Doravirine plasma concentrations declined in a single exponential phase (Figure 1), with an apparent terminal half-life of 12 to 19 h. Doravirine AUC0–∞, AUC0–24 h, Cmax and C24 h values increased in a slightly less than dose-proportional manner (Table 4). When doravirine 50 mg was administered with a high-fat meal, the median Tmax was 5.0 h, AUC0–∞ and C24 h increased slightly (fed/fasted geometric mean ratios [GMRs] and 90% CIs: 1.33 [1.12, 1.57] and 1.56 [1.28, 1.91], respectively), and Cmax remained unchanged (GMR [90% CI]: 0.95 [0.78, 1.16]). Over a 24-h period, 6.29% of a single 50-mg dose (in the fasted state) was excreted unchanged in the urine and the mean observed renal clearance was 9.43 ml/min. Consistent with single-dose results, multiple-dose data indicate that doravirine is rapidly absorbed (Tables 5 and 6). The median Tmax values on days 1 and 10 (or 1 and 14 for the 120-mg dose) ranged from 1.0 to 4.0 h. After 10–14 days of once-daily dosing, doravirine plasma concentrations declined in a single exponential phase (Figure 2), with an apparent terminal half-life of 13 to 21 h. Most subjects achieved steady state by day 7. Steady state AUC0–24 h and Cmax increased in a slightly less than dose-proportional manner, as was observed during single-dose administration. At steady 399
26/06/2015 16:23:48
MS Anderson et al.
Table 4. Summary statistics of pharmacokinetic parameters of doravirine after single oral doses in healthy males Apparent Dose, mg AUC0–∞, µM•ha AUC0–24 h, µM•ha Cmax, nMa C24 h, nMa Tmax, hb terminal t1/2, hc Study 1 6 12 25 50 50d 100 150 300 450 Study 2 600 800 1,000 1,200
2.88 (2.36, 3.51) 4.80 (3.94, 5.86) 11.21 (9.20, 13.66) 17.66 (14.47, 21.56) 23.48 (19.23, 28.67) 38.32 (31.46, 46.66) 50.16 (41.14, 61.15) 92.54 (75.92, 112.80) 126.58 (103.93, 154.16)
2.03 (1.71, 2.40) 3.62 (3.05, 4.29) 7.02 (5.92, 8.32) 12.68 (10.68, 15.04) 15.88 (13.39, 18.84) 22.84 (19.28, 27.06) 34.09 (28.76, 40.41) 58.87 (49.66, 69.78) 82.41 (69.56, 97.62)
156.10 (126.79, 192.18) 294.70 (239.13, 363.19) 461.27 (374.33, 568.41) 1,067.35 (864.84, 1,317.27) 1,017.43 (824.40, 1,255.67) 1,713.17 (1,391.54, 2,109.15) 2,653.72 (2,153.30, 3,270.44) 3,821.27 (3,101.00, 4,708.85) 6,012.15 (4,883.42, 7,401.78)
43.95 1.00 (1.00, 4.00) (35.26, 54.79) 71.50 1.00 (1.00, 3.00) (57.30, 89.23) 193.71 5.00 (1.00, 6.00) (155.25, 241.69) 269.52 1.00 (1.00, 4.00) (215.63, 336.86) 421.67 5.00 (3.00, 6.00) (337.37, 527.03) 593.43 1.50 (1.00, 5.00) (476.08, 739.71) 758.88 1.50 (1.00, 4.00) (608.14, 946.99) 1,490.08 3.50 (2.00, 5.00) (1,194.25, 1,859.21) 2,068.88 2.00 (1.00, 5.00) (1,659.77, 2,578.84)
11.68 (10.0)
145.61 (121.66, 174.26) 179.14 (149.68, 214.39) 215.93 (180.42, 258.42) 246.12 (205.65, 294.56)
100.91 (86.49, 117.75) 117.96 (101.09, 137.63) 137.73 (118.04, 160.70) 152.39 (130.60, 177.81)
7,416.43 (6,175.06, 8,907.35) 8,179.25 (6,810.20, 9,823.53) 10,085.62 (8,397.47, 12,113.12) 10,788.58 (8,982.78, 12,957.41)
2,243.93 (1,833.50, 2,746.23) 2,572.98 (2,102.36, 3,148.93) 3,199.65 (2,614.42, 3,915.89) 3,635.73 (2,970.73, 4,449.58)
2.50 (0.50, 4.00)
13.58 (14.1)
4.00 (2.00, 5.00)
16.45 (27.0)
2.00 (0.50, 5.00)
15.42 (11.0)
3.00 (1.00, 5.00)
18.88 (34.2)
11.67 (15.7) 15.67 (20.4) 13.29 (10.6) 13.07 (12.0) 15.26 (44.0) 13.84 (27.6) 15.62 (27.1) 14.80 (34.5)
Back-transformed least-squares mean and 95% CI from linear mixed-effects model performed on natural log-transformed values. bMedian (min, max). cGeometric mean (geometric mean percent coefficient of variation). dAfter a high-fat meal; other doses were given in the fasted state. AUC0–∞, area under the plasma concentration–time curve from time zero to infinity; AUC0–24 h, area under the plasma concentration–time curve during the dosing interval; Cmax, maximum plasma concentration; C24 h, trough plasma concentration; Tmax, time to maximum plasma concentration; t1/2, half-life. a
state, the mean AUC0–24 h, Cmax and C24 h accumulation ratios, expressed as the day 10/day 1 GMRs (or day 14/ day 1 GMRs for the 120-mg dose) were 1.1 to 1.5, consistent with predictions from single-dose data. However, some variability in individual accumulation ratios was noted. The observed AUC0–24 h accumulation ratios at each dose correspond to a mean effective accumulation half-life of approximately 9 to 14 h. The overall shape of the single-dose midazolam concentration–time profile was similar whether administered alone or with doravirine 120 mg at steady state (Additional file 1). Midazolam exposure (AUC0–∞) was slightly decreased in the presence of doravirine (GMR [90% CI] 0.82 [0.70, 0.97]), while Cmax was unchanged (GMR [90% CI] 1.02 [0.81, 1.28]; Table 7).
Safety Study 1: 34 subjects reported a total of 98 non-serious clinical adverse events. Of the 37 adverse events considered possibly or probably related to study drug, 26 400
AVT-14-OA-3365_Anderson.indd 400
occurred in subjects who received doravirine: headache (12), back pain (2), dizziness (2), somnolence (2), abdominal discomfort (1) or pain (1), dysgeusia (1), fatigue (1), feeling hot (1), involuntary leg muscle contractions (1), loose stools (1) and neck stiffness (1). Doravirine (120 mg once daily) was discontinued in one subject due to slightly elevated aspartate transaminase (AST; 1.6× upper limit of normal [ULN]) with normal alanine aminotransferase (ALT; 0.71×ULN) and very high creatine kinase (CK; 15.0×ULN) on day 5. These values peaked on day 7 (AST 2.8×ULN, ALT 1.1×ULN, CK 30.4×ULN) and declined to within normal range over the next 7 days. The subject did not report any clinical symptoms at any time during this period. This event was judged to be related to muscle damage due to patient-reported heavy physical activity, possibly aggravated by the concomitant use of doravirine. A second subject, who received placebo to match 30 mg doravirine, withdrew consent for personal reasons following the day 4 dose ©2015 International Medical Press
26/06/2015 16:23:48
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
Figure 1. Mean doravirine plasma concentration versus time profile following single doses of doravirine, 6 to 1,200 mg, in healthy male subjects
100,000 10,000 12,000
Mean doravirine plasma concentration, nM
1,000 10,000
100 10
8,000
1 6,000
0
12
24
36
48
60
72
84
96
108 120
4,000
2,000
0 0
12
24
36
48
60
6 mg 12 mg 25 mg 50 mg 100 mg 150 mg 50 mg with food 300 mg 450 mg 600 mg 800 mg 1,000 mg 1,200 mg
72
Time, h
Linear scale, first 72 h post-dose. Inset: semi-log scale.
Table 5. Summary statistics of pharmacokinetic parameters of doravirine after once-daily oral doses in fasted healthy males (study 1) Apparent Dose, mg Day n AUC0–24 h, µM•ha Cmax, nMa C24 h, nMa Tmax, hb terminal t1/2, hc 30
GMRd 60 GMRd 120 GMRd 240 GMRd
1 6 10 6 10/1 6 1 6 10 6 10/1 6 1 8 14 7e 14/1 7 1 6 10 6 10/1 6
8.42 (6.49, 10.92) 11.46 (8.84, 14.87) 1.36 (1.19, 1.56) 14.10 (10.87, 18.28) 17.33 (13.36, 22.48) 1.23 (1.07, 1.41) 27.31 (21.81, 34.21) 36.79 (29.22, 46.32) 1.35 (1.19, 1.53) 43.75 (33.73, 56.75) 60.59 (46.72, 78.58) 1.38 (1.21, 1.59)
671.52 (515.32, 875.08) 795.73 (610.63, 1,036.93) 1.18 (0.99, 1.42) 1,023.60 (785.50, 1,333.89) 1,303.22 (1,000.07, 1,698.26) 1.27 (1.07, 1.52) 1,920.63 (1,527.08, 2,415.61) 2,517.95 (1,985.69, 3,192.88) 1.31 (1.11, 1.54) 3,243.23 (2,488.80, 4,226.35) 4,474.70 (3,433.81, 5,831.12) 1.38 (1.16, 1.65)
177.02 (125.16, 250.37) 245.71 (173.73, 347.52) 1.39 (1.17, 1.64) 335.50 (237.22, 474.52) 384.66 (271.97, 544.05) 1.15 (0.97, 1.36) 670.92 (496.92, 905.84) 874.72 (644.19, 1,187.73) 1.30 (1.12, 1.52) 1,062.36 (751.13, 1,502.54) 1,340.65 (947.90, 1,896.14) 1.26 (1.07, 1.49)
1.00 (1.00, 5.00) 3.50 (1.00, 5.00) – 3.00 (1.00, 4.02) 2.00 (1.00, 4.00) – 2.00 (1.00, 4.00) 4.00 (1.00, 5.00) – 1.50 (1.00, 5.00) 3.00 (1.00, 5.00) –
NA 13.63 (11.3) – NA 12.59 (18.3) – NA 14.99 (22.9) – NA 13.35 (15.9) –
Back-transformed least-squares mean and 95% CI from linear mixed-effects model performed on natural log-transformed values. bMedian (min, max). cGeometric mean (geometric mean percent coefficient of variation). dDay 10 or 14/day1: back-transformed geometric mean ratio (GMR) and 90% CI from linear mixed-effects model performed on natural log-transformed values. eOne subject was excluded due to insufficient pharmacokinetic sampling. AUC0–24 h, area under the plasma concentration–time curve during the dosing interval; Cmax, maximum plasma concentration; C24 h, trough plasma concentration; NA, not applicable; Tmax, time to maximum plasma concentration; t1/2, half-life. a
Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 401
401
26/06/2015 16:23:48
MS Anderson et al.
Table 6. Summary statistics of pharmacokinetic parameters of doravirine after once-daily oral doses in fasted healthy males (study 2) Apparent Dose, mg Day n AUC0–24 h, µM•ha Cmax, nMa C24 h, nMa Tmax, hb terminal t1/2, hc 450
GMRd 750 GMRd
1 6 10 6 10/1 6 1 6 10 5e 10/1 5e
81.98 (70.21, 95.72) 100.10 (85.74, 116.88) 1.22 (1.13, 1.32) 99.15 (84.92, 115.76) 137.77 (117.59, 161.40) 1.39 (1.28, 1.51)
5,578.49 (4,814.61, 6,463.55) 7,589.78 (6,550.50, 8,793.95) 1.36 (1.15, 1.61) 6,976.13 (6,020.88, 8,082.94) 10,498.37 (8,909.63, 12,370.41) 1.50 (1.26, 1.79)
1,936.40 (1,516.41, 2,472.71) 2,092.18 (1,638.40, 2,671.64) 1.08 (0.95, 1.23) 2,367.85 (1,854.27, 3,023.66) 2,854.57 (2,219.84, 3,670.79) 1.21 (1.04, 1.39)
3.00 (1.00, 4.00) 1.50 (1.00, 4.00) – 3.00 (1.00, 5.00) 1.00 (0.52, 5.00) –
NA 14.67 (30.5) – NA 20.95 (55.1) –
Back-transformed least-squares mean and 95% CI from linear mixed-effects model performed on natural log-transformed values. bMedian (min, max). cGeometric mean (geometric mean percent coefficient of variation). dDay 10/day1: back-transformed geometric mean ratio (GMR) and 90% CI from linear mixed-effects model performed on natural log-transformed values. eOne subject was excluded due to insufficient pharmacokinetic sampling. AUC0–24 h, area under the plasma concentration– time curve during the dosing interval; Cmax, maximum plasma concentration; C24 h, trough plasma concentration; NA, not applicable; Tmax, time to maximum plasma concentration; t1/2, half-life. a
and discontinued from the study. No serious adverse events were reported, and there were no consistent, clinically relevant, treatment-related effects of doravirine on vital signs or ECGs. Study 2: 14 subjects reported a total of 104 nonserious clinical adverse events. Of the 38 adverse events considered possibly related to study drug, 30 occurred in subjects who received doravirine: headache (17), nausea (4), fatigue (2), somnolence (2), stomach discomfort (1), irritability (1), musculoskeletal chest pain (1), neck pain (1) and vomiting (1). All of the non-serious clinical adverse events were mild or moderate in intensity and of limited duration. One serious adverse event of sarcoidosis was reported after administration of 750 mg doravirine once daily for 7 days. This event was determined to be probably not drug related, due to a medical history of multiple preceding upper respiratory infections and a histopathological examination of enlarged mediastinal lymph nodes biopsied during the study that revealed granulomas. The findings supported the investigator’s conclusion that sarcoidosis was likely a pre-existing condition. Overall, no clinically significant trends or signals were observed in laboratory assessments, vital signs or ECGs.
Discussion The safety, tolerability and pharmacokinetics of doravirine were investigated in two single- and multipleascending dose studies that explored a wide range of doses (6 to 1,200 mg) in healthy male subjects. Doravirine was rapidly absorbed after both single-dose and multiple-dose administration, with median Tmax values of 1 to 5 h post-dose. Thereafter, concentrations declined in a single exponential phase, with an apparent terminal half-life of 12 to 21 h. AUC and Cmax values increased in a slightly less than dose-proportional manner after both single- and multiple-dose administration. After multiple days of once-daily dosing, most 402
AVT-14-OA-3365_Anderson.indd 402
subjects achieved steady state by day 7. The observed AUC0–24 h accumulation ratios of 1.2 to 1.4 correspond to a mean effective accumulation half-life of approximately 9 to 14 h. For the NNRTI and protease inhibitor classes of antiretroviral agents, there is a general association of efficacy with doses that achieve trough concentration values exceeding the protein-adjusted IC95 in the HIV spread assay, in which IC95 is defined as the concentration at which replication/reinfection of the virus in a cell culture setting is inhibited by >95% in the presence of 50% normal human serum [3]. These pharmacokinetic/pharmacodynamic relationships have been supported by experiments using an in vitro hollow-fibre bioreactor system where exposure of HIV-infected cells to each inhibitor class can be carefully controlled over time [4]. Using time above trough concentration as the key parameter, population pharmacokinetic modelling for one novel NNRTI has successfully predicted clinical effects on HIV viral load in a Phase Ib proofof-concept study [5]. In the current study, single doses of doravirine, 12 mg and higher, resulted in geometric mean C24 h exceeding the in vitro IC95 in 50% human serum of not only wild-type virus (IC95 19 nM), but also that of several common efavirenz resistance mutations, including the double mutant K103N/Y181C (IC95 54 nM). These trough levels were durably sustained following multiple once-daily dosing. These results were utilized as one factor in dose selection for the subsequent Phase II dose-ranging study in HIVinfected patients [6]. After administration of a single 50-mg dose, only a minimal amount of doravirine was excreted unchanged in the urine (6.3% over a 24-h period), while mean observed renal clearance was low (9.43 ml/min). These results suggest that urinary excretion is not a major route of doravirine elimination. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC0–∞ and C24 h with no change in Cmax. This food effect is unlikely to ©2015 International Medical Press
26/06/2015 16:23:49
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
Figure 2. Mean doravirine plasma concentration versus time profile following once daily oral doses of doravirine, 30 to 750 mg, for 10 or 14 days in healthy male subjects
Mean doravirine plasma concentration, nM
12,000
10,000 30 mg ×10 days 60 mg ×10 days 120 mg ×14 days 240 mg ×10 days 450 mg ×10 days 750 mg ×10 days
8,000
6,000
4,000
2,000
0 0
12
24 3
5
Time, h
7
9
11
13 0
12
24
36
48
Day
60
72
84
96
108
120
84
96
108
120
Time, h
Day 1
Day 10 or 14
Mean doravirine plasma concentration, nM
100,000
10,000
1,000
100
10
1 0
12
24 3
Time, h
5
7
9
11
13 0
Day
Day 1
12
24
36
48
60
72
Time, h Day 10 or 14
Upper plot: linear; lower plot: semi-log.
be clinically meaningful, although continued development will clarify pharmacokinetic/pharmacodynamic relationships. In vitro studies predict that doravirine has low potential to be a perpetrator of drug interactions via CYP metabolism. In the current study, midazolam exposure was decreased by approximately 18% Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 403
in the presence of doravirine, while Cmax remained unchanged with concomitant doravirine administration. As midazolam is a sensitive CYP3A4 substrate, these results support the position that doravirine is not a significant inhibitor of CYP3A4 metabolism and also suggest that doravirine may be a weak inducer of CYP3A4. 403
26/06/2015 16:23:49
MS Anderson et al.
Table 7. Statistical comparison of pharmacokinetic parameters after midazolam 2 mg alone or with multiple oral doses of doravirine 120 mg in healthy males Parameter
Midazolam (n=8)a
Doravirine + midazolam (n=7)a,b
(Doravirine + midazolam)/midazolamc
AUC0–∞, ng/ml•hd Cmax, ng/mld Tmax, he Apparent terminal t1/2, hf
32.87 (19.40, 55.68) 9.97 (6.83, 14.55) 1.0 (0.50–1.50) 3.81 (62.2)
26.98 (15.90, 45.78) 10.14 (6.90, 14.91) 0.5 (0.33–0.50) 3.41 (65.6)
0.82 (0.70, 0.97) 1.02 (0.81, 1.28) – –
a Values are geometric mean (GM [95% CI]) unless otherwise indicated. bOne subject had missing pharmacokinetic data when doravirine and midazolam were coadministered. cValues are geometric mean ratio (GMR [90% CI]). dBack-transformed least squares mean and CI from mixed effects model performed on natural logtransformed values. eValues are median (range). fValues are GM (geometric mean percent coefficient of variation [GCV]). GCV is calculated in the natural log-scale with the equation: 100× the square root (exp(s2)-1), where s2 is the observed variance on the natural log-scale. AUC0–∞, area under the plasma concentration–time curve from time zero to infinity; Cmax, maximum plasma concentration; Tmax, time to maximum plasma concentration; t1/2, half-life.
In these two studies of healthy male subjects, doravirine was generally well tolerated when given orally as single doses ranging from 6 to 1,200 mg and as multiple doses ranging from 30 to 750 mg once daily for 10–14 days. One serious adverse event (sarcoidosis) was reported in a subject receiving doravirine 750 mg once daily, but was judged probably not related to doravirine. All of the non-serious clinical adverse events were mild or moderate in intensity and of limited duration. No clinically significant trends or signals were observed in clinical laboratory assessments, vital signs or ECGs. In summary, the results of these studies indicate that doravirine is generally well tolerated and exhibits a pharmacokinetic profile supportive of once-daily dosing. Trough concentrations predictive of virological suppression of wild-type and of common NNRTI-resistant strains were achieved with single doses as low as 12 mg, and were maintained over 10 days of once-daily dosing. At steady state, doravirine 120 mg did not have a significant effect on midazolam exposure, consistent with in vitro studies suggesting that doravirine has limited potential for drug interactions mediated by CYP3A4. These results support the further clinical development of doravirine as a once-daily NNRTI. Based on the week 24 results of the Phase II, dose-finding study of doravirine 25, 50, 100 and 200 mg once daily in HIVinfected patients, the 100-mg dose of doravirine has been selected for further development [6].
Inc. The study was designed, managed and analysed by the sponsor in conjunction with external investigators. Authors had access to all study data upon request. All authors approved the final version of the manuscript for submission. The manuscript was also reviewed by the sponsor. The opinions expressed in the manuscript represent the collective views of the authors and do not necessarily reflect the official position of Merck or the institutions affiliated with the academic authors. LVB has received grants for clinical trial conduct from Merck, Janssen, GSK, Actogenix, Daiichi-Sankyo, Menarini and Yakult; speaker fees from Novartis, Janssen, Recordati, and AIM; and conference support from Servier and Daiichi-Sankyo. The remaining authors are current or former employees of Merck & Co., Inc. and may own stock and/or stock options in the company.
Additional file Additional file 1: Mean plasma concentration profiles of midazolam alone and coadministered with doravirine 120 mg once daily in healthy male subjects can be found at http://www.intmedpress.com/uploads/ documents/3365_Anderson_Addfile1.pdf
References 1.
Acknowledgements We thank the subjects who participated in this study, the clinical research unit staff, and Karyn Davis and Kim Strohmaier (both of Merck & Co., Inc., Kenilworth, NJ, USA) for medical writing assistance.
Disclosure statement This study was sponsored and funded by Merck, Sharp & Dohme Corp., a subsidiary of Merck & Co., 404
AVT-14-OA-3365_Anderson.indd 404
2.
3. 4.
de Béthune MP. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009). Antiviral Res 2010; 85:75–90. Lai MT. Antiviral activity and in vitro mutation development pathways of MK-1439: a novel non-nucleoside reverse transcriptase inhibitor (NNRTI). Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC). 9–12 September 2012, San Francisco, CA, USA. Abstract H551. Vacca JP, Dorsey BD, Schleif WA, et al. L-735,524: an orally bioavailable human immuno-deficiency virus type 1 protease inhibitor. Proc Natl Acad Sci U S A 1994; 91:4096–4100. Bilello JA, Bauer G, Dudley MN, Cole GA, Drusano GL. Effect of 2′,3′-didehydro-3′-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies. Antimicrob Agents Chemother 1994; 38:1386–1391. ©2015 International Medical Press
26/06/2015 16:23:49
Safety, tolerability and pharmacokinetics of doravirine in healthy subjects
5.
Drusano GL, Moore KH, Kleim JP, Prince W, Bye A. Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation. Antimicrob Agents Chemother 2002; 46:913–916.
6.
Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety & antiviral effect of MK-1439, a novel NNRTI, (+TDF/ FTC) in ART-naive HIV infected patients. Conference on Retroviruses and Opportunistic Infections (CROI). 3–6 March 2014, Boston, MA, USA. Abstract 92LB.
Accepted 31 October 2014; published online 3 December 2014
Antiviral Therapy 20.4
AVT-14-OA-3365_Anderson.indd 405
405
26/06/2015 16:23:49
