The
Teddy
Effect of Antacid and Cimetidine on the Oral Absorption of the Antifungal Agent SCH 39304
Kosoglou,
PharmD,
Chin-Chung
Lin,
George PhD,
P. Perentesis,
PharmD,
Parviz Mojaverian, and Peter H. Vlasses,
Melton
PhD, Elaine PharmD
B. Affrime, Radwanski,
PharmD, PhD,
The single-dose pharmacokinetics of the antifungal agent SCH 39304 (Schering-Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effecton any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304. as assessed by the area under the plasma concentration-time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC#{176}t for the drug given alone was 80.5 ± 15.8 tg#{149} hr/mL, compared to 81.4 ± 12.7 and 79.7 ± 9.6 tg - hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae#{176}1 was 22.7 ± 5.1, 24.2 ± 9.2, and 23.6 ± 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the t,,,. in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmocokinetic disposition of single-dose
SCH
39304.
S
CH 39304 is a new triazole antifungal agent with demonstrated in vitro and in vivo activity against a broad range of fungal pathogens. including Aspergillus, Candida, Cryptococcus, Histo plasma, and Trichophyton.1 Following oral administration, the drug is well absorbed and distributed widely in the body, including the central nervous system, with approximately 80% of the dose excreted unchanged in the urine.1 Initial pharmacokinetic studies have shown SCH 39304 to have a long elimination halflife of approximately 60 hours which is expected to permit once daily or alternate-day dosing.1 Results
From the Division of Clinical Pharmacology, Department of Medicine, Jefferson Medical College (Drs. Kosoglou and Vlasses), and the Depart. ments of Clinical Pharmacology and Drug Metabolism, Schering. Plough Research (Drs. Perentesis, Affrime, Lin, Molaverian, and Radwanski). Supported by a grant from Schering-Plough Corporation, Kenilworth, NJ. Address for reprints: Teddy Kosoglou, PharmD, Clinical Pharmacology (K.6-1, G-6), Schering.Plough Research, 2000 Galloping Hill Road, Kenilworth, NJ 07033.
638
#{149} J Clin Pharmacol
1990;30:638-642
from preclinical studies suggest that SCH 39304 may become an important drug for the prophylaxis and treatment of non-life-threatening as well as potentially fatal fungal infections in both immunocom-
promised
patients
and
those
with
normal
immune
function. Preliminary clinical trials show the drug to be safe and well tolerated in single oral doses of up to 200 mg.1 Previous studies have demonstrated that gastric alkalinization can significantly decrease the oral absorption of other antifungal agents such as ketoconazole leading to therapeutic failures.2-3 Cimetidine has been shown to reduce the gastric absorption and clearance of several drugs by a number of different mechanisms.4-5 Since SCH 39304, cimetidine, and antacids may be used concurrently in clinical practice, there is a potential for a significant drug interaction. Furthermore, since patients with acquired immunodeficiency syndrome (AIDS) who are prone to fungal infections, also tend to exhibit hypochlorhydria,6 it is important to demonstrate whether or not gastric alkalinization will affect this drug’s bio-
EFFECT
availability. to evaluate SCH 39304 and in the dine.
OF
ANTACID
AND
Therefore, the purpose of this study was the bioavailability of a single oral dose of given concomitantly with an antacid, presence of steady state levels of cimeti-
METHODS
CIMETIDINE
ON
SCH
39304
On the morning of the fourth day (study day 1), following an overnight fast, subjects received 300 mg of cimetidine orally at approximately 1 hour before administration of SCH 39304, and continued to take cimetidine for three more doses at approximately every 5 hours for a total of 16 doses. During the time that subjects were receiving cimetidine as outpa-
they were required to keep an accurate medication administration record which they returned to the investigator at the time of their CRU admission. tients,
Subjects Nine healthy men ranging in age from 22 to 31 years and weighing 61 to 82 kg were studied. All subjects were judged to be healthy on the basis of a normal history, physical examination, electrocardiogram (ECG) and laboratory tests of renal, hepatic, and hematopoietic function. Subjects did not consume any drugs (including over-the-counter preparations) for at least 7 days prior to and during the course of the study. Subjects were not permitted to drink alcoholic beverages 2 days prior to and throughout the study period. The study protocol was approved by the Institutional Review Board of Thomas Jefferson University. All subjects gave informed written consent prior to participating in the study.
Study
Protocol
This was an open label, randomized, three-period crossover study, with each treatment period separated by at least a 3-week drug-free period. Each of the nine subjects received SCH 39304 alone (treatment A), SCH 39304 ingested concurrently with an antacid (treatment B), and SCH 39304 given concurrently with cimetidine (treatment C), in a random sequence. At approximately 12 hours before the start of each study period, subjects were admitted to the Clinical Research Unit (CRU), were given a light dinner and subsequently fasted after 10:00 PM. The following morning, an intravenous indwelling catheter was placed in a forearm vein, and baseline blood and urine samples were collected. For treatment A, subjects received one 50 mg capsule of SCH 39304 (SCH 39304; Schering-Plough Corp., Kenilworth, NJ) with 120 mL of a water. For treatment B, subjects received one 50 mg capsule of SCH 39304 with 120 mL of a water, followed immediately by 60 mL of antacid suspension (Mylanta#{174}, Stuart Pharmaceuticals, Division of ICI Americas Inc., Wilmington, DE). For treatment C, subjects received cimetidine 300 mg tablets (Tagamet#{174}, Smith Kline & French Lab, Co. Cidra, Puerto Rico) orally four times a day (at approximately 8:00 AM, 1:00 PM, 6:00 PM, and 11:00 PM) for three days as outpatients.
ANTIBIOTIC/ANTIANGINAL
AGENTS
Blood samples (7-mL each) were collected into heparinized tubes (green-top Vacutainer#{174} tubes, Becton Dickinson and Company, Rutherford, NJ), just prior to (0 hour), and at 0.5, 1, 2,4, 6,8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours after the SCH 39304 dose. The samples were centrifuged and the plasma was immediately harvested and stored at -20#{176}C until analysis. Urine was collected predose and at 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours after SCH 39304 administration. The volume and pH of each urine collection was measured and recorded and subsequently 25 mL aliquots were stored at -20#{176}C until assay.
Analytic
Method
Plasma and urine samples were analyzed for SCH 39304 concentrations by high performance liquid chromatography (HPLC). Briefly, the procedure involved alkalization of 0.5 mL plasma or urine containing 800 ng of dextrorphan (internal standard) with 0.1 mL of 4.5 M ammonium hydroxide and extraction with 4 mL of 30% methylene chloride in hexane. After 10 minutes of shaking and 5 minutes of centrifugation at 3000 rpm, the organic layer was transferred into a clean tube and evaporated to dryness under a stream of nitrogen at 45 to 50#{176}C.Subsequently, the residue was dissolved in 0.2 mL of mobile phase (15% acetonitrile and 1.6% tetrahydrofuran in 0.02 M monobasic potassium phosphate buffer, pH 4.5), and 20 to 50 tL were injected into the column (C18, 4.6 mm )< 50 cm). The interday and intraday coefficients of variation for the assay were .05). Analysis of individual time points for which all data were at or above assay sensitivity (hours 2-144) indicated a significant treatment effect only for hour 2 (P = .01). Pairwise comparison results at hour 2 showed the mean value for SCH 39304 given alone (0.77 ig/mL) to be significantly lower (P
Teddy
Effect of Antacid and Cimetidine on the Oral Absorption of the Antifungal Agent SCH 39304
Kosoglou,
PharmD,
Chin-Chung
Lin,
George PhD,
P. Perentesis,
PharmD,
Parviz Mojaverian, and Peter H. Vlasses,
Melton
PhD, Elaine PharmD
B. Affrime, Radwanski,
PharmD, PhD,
The single-dose pharmacokinetics of the antifungal agent SCH 39304 (Schering-Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effecton any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304. as assessed by the area under the plasma concentration-time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC#{176}t for the drug given alone was 80.5 ± 15.8 tg#{149} hr/mL, compared to 81.4 ± 12.7 and 79.7 ± 9.6 tg - hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae#{176}1 was 22.7 ± 5.1, 24.2 ± 9.2, and 23.6 ± 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the t,,,. in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmocokinetic disposition of single-dose
SCH
39304.
S
CH 39304 is a new triazole antifungal agent with demonstrated in vitro and in vivo activity against a broad range of fungal pathogens. including Aspergillus, Candida, Cryptococcus, Histo plasma, and Trichophyton.1 Following oral administration, the drug is well absorbed and distributed widely in the body, including the central nervous system, with approximately 80% of the dose excreted unchanged in the urine.1 Initial pharmacokinetic studies have shown SCH 39304 to have a long elimination halflife of approximately 60 hours which is expected to permit once daily or alternate-day dosing.1 Results
From the Division of Clinical Pharmacology, Department of Medicine, Jefferson Medical College (Drs. Kosoglou and Vlasses), and the Depart. ments of Clinical Pharmacology and Drug Metabolism, Schering. Plough Research (Drs. Perentesis, Affrime, Lin, Molaverian, and Radwanski). Supported by a grant from Schering-Plough Corporation, Kenilworth, NJ. Address for reprints: Teddy Kosoglou, PharmD, Clinical Pharmacology (K.6-1, G-6), Schering.Plough Research, 2000 Galloping Hill Road, Kenilworth, NJ 07033.
638
#{149} J Clin Pharmacol
1990;30:638-642
from preclinical studies suggest that SCH 39304 may become an important drug for the prophylaxis and treatment of non-life-threatening as well as potentially fatal fungal infections in both immunocom-
promised
patients
and
those
with
normal
immune
function. Preliminary clinical trials show the drug to be safe and well tolerated in single oral doses of up to 200 mg.1 Previous studies have demonstrated that gastric alkalinization can significantly decrease the oral absorption of other antifungal agents such as ketoconazole leading to therapeutic failures.2-3 Cimetidine has been shown to reduce the gastric absorption and clearance of several drugs by a number of different mechanisms.4-5 Since SCH 39304, cimetidine, and antacids may be used concurrently in clinical practice, there is a potential for a significant drug interaction. Furthermore, since patients with acquired immunodeficiency syndrome (AIDS) who are prone to fungal infections, also tend to exhibit hypochlorhydria,6 it is important to demonstrate whether or not gastric alkalinization will affect this drug’s bio-
EFFECT
availability. to evaluate SCH 39304 and in the dine.
OF
ANTACID
AND
Therefore, the purpose of this study was the bioavailability of a single oral dose of given concomitantly with an antacid, presence of steady state levels of cimeti-
METHODS
CIMETIDINE
ON
SCH
39304
On the morning of the fourth day (study day 1), following an overnight fast, subjects received 300 mg of cimetidine orally at approximately 1 hour before administration of SCH 39304, and continued to take cimetidine for three more doses at approximately every 5 hours for a total of 16 doses. During the time that subjects were receiving cimetidine as outpa-
they were required to keep an accurate medication administration record which they returned to the investigator at the time of their CRU admission. tients,
Subjects Nine healthy men ranging in age from 22 to 31 years and weighing 61 to 82 kg were studied. All subjects were judged to be healthy on the basis of a normal history, physical examination, electrocardiogram (ECG) and laboratory tests of renal, hepatic, and hematopoietic function. Subjects did not consume any drugs (including over-the-counter preparations) for at least 7 days prior to and during the course of the study. Subjects were not permitted to drink alcoholic beverages 2 days prior to and throughout the study period. The study protocol was approved by the Institutional Review Board of Thomas Jefferson University. All subjects gave informed written consent prior to participating in the study.
Study
Protocol
This was an open label, randomized, three-period crossover study, with each treatment period separated by at least a 3-week drug-free period. Each of the nine subjects received SCH 39304 alone (treatment A), SCH 39304 ingested concurrently with an antacid (treatment B), and SCH 39304 given concurrently with cimetidine (treatment C), in a random sequence. At approximately 12 hours before the start of each study period, subjects were admitted to the Clinical Research Unit (CRU), were given a light dinner and subsequently fasted after 10:00 PM. The following morning, an intravenous indwelling catheter was placed in a forearm vein, and baseline blood and urine samples were collected. For treatment A, subjects received one 50 mg capsule of SCH 39304 (SCH 39304; Schering-Plough Corp., Kenilworth, NJ) with 120 mL of a water. For treatment B, subjects received one 50 mg capsule of SCH 39304 with 120 mL of a water, followed immediately by 60 mL of antacid suspension (Mylanta#{174}, Stuart Pharmaceuticals, Division of ICI Americas Inc., Wilmington, DE). For treatment C, subjects received cimetidine 300 mg tablets (Tagamet#{174}, Smith Kline & French Lab, Co. Cidra, Puerto Rico) orally four times a day (at approximately 8:00 AM, 1:00 PM, 6:00 PM, and 11:00 PM) for three days as outpatients.
ANTIBIOTIC/ANTIANGINAL
AGENTS
Blood samples (7-mL each) were collected into heparinized tubes (green-top Vacutainer#{174} tubes, Becton Dickinson and Company, Rutherford, NJ), just prior to (0 hour), and at 0.5, 1, 2,4, 6,8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours after the SCH 39304 dose. The samples were centrifuged and the plasma was immediately harvested and stored at -20#{176}C until analysis. Urine was collected predose and at 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours after SCH 39304 administration. The volume and pH of each urine collection was measured and recorded and subsequently 25 mL aliquots were stored at -20#{176}C until assay.
Analytic
Method
Plasma and urine samples were analyzed for SCH 39304 concentrations by high performance liquid chromatography (HPLC). Briefly, the procedure involved alkalization of 0.5 mL plasma or urine containing 800 ng of dextrorphan (internal standard) with 0.1 mL of 4.5 M ammonium hydroxide and extraction with 4 mL of 30% methylene chloride in hexane. After 10 minutes of shaking and 5 minutes of centrifugation at 3000 rpm, the organic layer was transferred into a clean tube and evaporated to dryness under a stream of nitrogen at 45 to 50#{176}C.Subsequently, the residue was dissolved in 0.2 mL of mobile phase (15% acetonitrile and 1.6% tetrahydrofuran in 0.02 M monobasic potassium phosphate buffer, pH 4.5), and 20 to 50 tL were injected into the column (C18, 4.6 mm )< 50 cm). The interday and intraday coefficients of variation for the assay were .05). Analysis of individual time points for which all data were at or above assay sensitivity (hours 2-144) indicated a significant treatment effect only for hour 2 (P = .01). Pairwise comparison results at hour 2 showed the mean value for SCH 39304 given alone (0.77 ig/mL) to be significantly lower (P
