Antihypertensive effect and pharmacokinetics of nitrendipine in children T h o m a s G, Wells, MD, a n d A l a n R. S i n a i k o , MD From the Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, and the Departments of Pediatrics and Pharmacology, University of Minnesota Medical School, Minneapolis
Nitrendipine, a new calcium-channel antagonist, was used to treat 25 children ( a g e d 6 months to 17 years) with severe hypertension. Systolic and diastolic blood pressures(mean _+ SEM)fell from 148 _+ 2/99 _+ 2 mm Hgto 128 _ 4/77 _ 3 mm Hg after 24 hours and to 121 _+ 2/75 _+ 2 mm Hg after 2 weeks. No further reductions in systolic or diastolic blood pressure were observed after continued therapy. Transient reflex tachycardia occurred during the first w e e k of therapy. Other adverse effects were uncommon and included headaches, flushing, palpitations, and e d e m a . Pharmacokinetic parameters were estimated at steady state after an oral dose of 0.56 _ 0.04 m g / k g in 13 children. Although absolute oral bioavailabllity could not be determined, estimates of the area under the plasma concentration versus time curve, the apparent peak serum concentration, and the apparent time at which the peak serum concentration occurred indicated that both the rate of absorption and oral bloavailability are variable. Coadministration of nitrendipine with food decreased the rate of absorption and may have reduced oral bioavailability. A relationship between a g e and the apparent plasma elimination half-life of nitrendipine was not observed. Nitrendipine, 0.25 to 0.5 m g / k g per dose administered orally every 6 to 12 hours, appeared to be an effective and safe treatment for resistant hypertension in infants and children. (J PEDIATR1991;118:638-43)
Nitrendipine, a new calcium-channel antagonist, is a substituted 1,4-dihydropyridine derivative with a molecular structure and mechanism of action similar to those of nifedipine.1 Both drugs antagonize transmembrane calcium flux in peripheral vascular smooth muscle, resulting in decreased peripheral vascular resistance and vasodilation.2 Although nifedipine has been used successfully to treat hypertension in children and adutts, 36 its relatively short duration of action has limited its usefulness as a long-term antihypertensive agent in children), 4 In contrast, results of studies in adults have shown nitrendipine to have a longer
duration of action than nifedipine and to reduce blood pressure when administered twice daily. 7 This report details the pharmacokinetic and pharmacodynamic data from a series of 25 children with hypertension treated with nitrendipine for up to 12 weeks.
Supported by National Research Service Award 5 F32 DK0776401, Miles Laboratories. Submitted for publication Aug. 30, 1990; accepted Nov. 16, 1990. Reprint requests: Thomas G. Wells, MD, Arkansas Children's Hospital, 800 Marshall St., Little Rock, AR 72202. 9/25/26568
METHODS
638
AUCss
Clnax K~
Trnax
Area under the plasma concentration versus time curve at steady state Apparent peak serum concentration Elimination rate constant Apparent time at which peak serum concentration occurred
Children participating in this study were patients at the University of Minnesota Hospital and Clinics and were hospitalized for at least 24 hours before and 48 hours after initiation of nitrendipine therapy. Patients were eligible to
Volume 118 Number 4, Part 1
receive nitrendipine if systolic and diastolic blood pressure was persistently above the 95th percentile for age and gender. 8 Patients with congestive heart failure, arrhythmias, or malignancy were excluded from the study. This protocol was approved by the University of Minnesota Committee on the Use of Human Subjects in Research. Written consent for participation was obtained from parents and when appropriate from patients. Study design. Blood pressure and heart rate were measured by means of standard techniques with patients in the supine position. 8 A Dinamap oscillometric blood pressure recorder (Critikon, Inc., Tampa, Fla.) was used in patients less than 2 years of age and during dose titration in several older patients. A standard mercury sphygmomanometer was used in all other children. Blood pressure cuff size was chosen according to published guidelines. 8 Regularly scheduled antihypertensive therapy was not changed unless subjects were receiving nifedipine, which was discontinued before nitrendipine was started. Intravenous vasodilators were not administered during the initial dose titration of nitrendipine. Nitrendipine was supplied in tablet form by Miles, Inc., West Haven, Conn. Tablets were fragmented and suspended in water (10 ml or less) for children unable to swallow whole tablets. All doses of nitrendipine were administered orally with water. A cumulative dose-titration protocol was used. After baseline blood pressure and heart rate were determined, an initial dose of 0.1 mg/kg of nitrendipine was administered. Blood pressure and heart rate measurements were repeated every 15 minutes. If systolic or diastolic pressure remained above the 95th percentile for age 8 3 hours after the first dose, a second dose of nitrendipine, 0.25 mg/kg, was administered. If blood pressure remained above the 95th percentile 3 hours later, a third dose (0.5 mg/kg) was given. Beginning with the ninth patient, the protocol was modified by increasing the initial dose of nitrendipine to 0.25 mg/kg. A single subsequent dose of 0.5 mg/kg was administered to patients who did not respond. The total daily dose of nitrendipine was limited to 3 mg/kg per 24 hours or a maximum of 80 mg in 24 hours. The maintenance dose of nitrendipine was determined by the response of individual patients during dose titration and was administered initially every 12 hours. Changes in the maintenance dose and dosing interval were made at the discretion of the investigators according to changes in blood pressure. In patients with blood pressures persistently above the 95th percentile after 96 hours of therapy, treatment was considered unsuccessful and nitrendipine was discontinued. To assess the long-term effect of nitrendipine on blood pressure and heart rate in children, we obtained measurements after 24 hours and 1, 2, 4, 8, and 12 weeks.
Nitrendipine for hypertension
639
Laboratory procedures.The following laboratory results were obtained from each patient before they entered the study: complete blood cell count, urinalysis, and serum levels of sodium, potassium, chloride, bicarbonate, total and ionized calcium, phosphate, albumin, total protein, glucose, cholesterol, triglycerides, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, uric acid, blood urea nitrogen, and creatinine. An electrocardiogram, chest roentgenogram, and echocardiogram were obtained from each patient. Determinations of serum levels of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, and total and ionized calcium were repeated 24 hours, 7 days, 4 weeks, and 12 weeks after nitrendipine was started. All other tests, with the exception of chest roentgenography, were repeated after 12 weeks or when nitrendipine was discontinued. Glomerular filtration rate was estimated according to the method of Schwartz et al. 9 Analysis of the disposition of nitrendipine was studied in 13 patients on a stable dosing regimen for a minimum of 5 days. Serial blood samples were collected before and 30 minutes and 1, 2, 3, 4, and 6 hours after an oral dose of nitrendipine. Samples were collected at 8 hours from patients with longer dosing intervals. After centrifugation, plasma was removed and stored at - 2 0 ~ C until shipment in dry ice to Miles Laboratories. Nitrendipine concentrations were measured by Dr. George Krol with capillary gas chromatography. 1~ Data analysis. All patient data are expressed as mean ___ SEM. Individual plasma concentration versus time data were evaluated with S I P H A R / B a s e (SIMED, Creteil, France). Initial polyexponential parameter estimates were generated with the use of a peeling algorithm) 1 Final parameter estimates were obtained from a nonlinear, weighted least-squares algorithm with the weight set as the reciprocal of the calculated concentration) 2 Compartment model selection was made after application of Akaike's information criterion. 13 Finally compartment model-dependent pharmacokinetic parameters were calculated by previously described methods) 4 Pharmacokinetic parameters are expressed as mean ___SEM. Differences between pretherapy and posttherapy physiologic measurements and laboratory findings were analyzed with a two-tailed Student t test for paired data with Bonferroni correction. 15 To compare the number of patients who became normotensive after receiving initial doses of either 0.1 or 0.25 mg/kg, a two-tailed Fisher Exact Test was used because fewer than five patients were present in at least one cell of the 2 X 2 contingency tables. 16 Possible relationships between age, renal function, and pharmacokinetic parameters were examined by means of least-squares linear regression. 15 Differences between pharmacokinetic param-
640
Wells and S i n a i k o
The Journal o f Pediatrics April 1991
n= 25
25
25
22
25
21
18
180
140 N
=
Sys BP (mmHg)
o-~
Dias BP (mmHg)
t
]E
120
Blood Pressure (mmHg) 100
80
60
I
I
I
[
I
I
I
Baseline
24 Hrs
1 Wk
2 Wk
4 Wk
8 Wk
12 Wk
Duration of Therapy Figure. Systolic and diastolic blood pressure responses (mean _+ SEM) during long-term therapy with nitrendipine. Asterisk indicates blood pressure significantly lower than baseline (p 0.05 in comparison with the lower dose). Long-term therapy with nitrendipine. On the basis of the results of the dose-titration study, maintenance therapy was started at 0.1 mg/kg per dose in one patient, 0.25 mg/kg per dose in four patients, and 0.5 mg/kg per dose in 20 patients. Nitrendipine initially was administered twice daily. Because of the inadequate duration of the antihypertensive response, the dosing interval was decreased to 8 hours in 19 patients and 6 hours in four. The mean daily doses of nitrendipine during maintenance therapy ranged from 1.33 _+ 0.66 to 1.58 _+ 0.49 mg/kg. Systolic and diastolic blood pressure continued to fall during the first week of therapy and remained significantly
Volume 118 Number 4, Part 1
Nitrendipine for hypertension
Table
Table I Pharmacokinetic parameters
Dose (mg/kg) Cmax (ng/ml) Tmax (hr) AUCss (ng/ml*hr) Kc (hr -1) Elimination half-life (hr)
Patient d a t a
0.56 + 0.04 34.7 _+ 9.1 1.5 - 0.3 86.0 + 19.0 0.28 _+ 0.04 2.5
(0.25-0.74) (7.1-110.8) (0.5-4.0) (13.3-210) (0.11-0.49) (1.4-6.3)
641
II
Pharmacokinetic parameters
Dose (mg/kg) Cmax (ng/ml) Tmax (hr)
AUCss (ng/ml*hr) Kc(hr-1) Elimination half-life (hr)
Fasting (n = 5)
Nonfasting (n = 5)
0.57 _+ 0.05 71 _+ 10 1.0 _+ 0.3 158 _+ 20 0.32 _+ 0.07 2.2 (1.4-6.3)
0.59 + 0.05 13 _+ 3* 2.4 _+ 0.5* 46 _+ 16" 0.33 +_ 0.06 2.1 (1.6-5.1)
*Significantlydifferentfromfastingpatients(a
Nitrendipine, a new calcium-channel antagonist, was used to treat 25 children ( a g e d 6 months to 17 years) with severe hypertension. Systolic and diastolic blood pressures(mean _+ SEM)fell from 148 _+ 2/99 _+ 2 mm Hgto 128 _ 4/77 _ 3 mm Hg after 24 hours and to 121 _+ 2/75 _+ 2 mm Hg after 2 weeks. No further reductions in systolic or diastolic blood pressure were observed after continued therapy. Transient reflex tachycardia occurred during the first w e e k of therapy. Other adverse effects were uncommon and included headaches, flushing, palpitations, and e d e m a . Pharmacokinetic parameters were estimated at steady state after an oral dose of 0.56 _ 0.04 m g / k g in 13 children. Although absolute oral bioavailabllity could not be determined, estimates of the area under the plasma concentration versus time curve, the apparent peak serum concentration, and the apparent time at which the peak serum concentration occurred indicated that both the rate of absorption and oral bloavailability are variable. Coadministration of nitrendipine with food decreased the rate of absorption and may have reduced oral bioavailability. A relationship between a g e and the apparent plasma elimination half-life of nitrendipine was not observed. Nitrendipine, 0.25 to 0.5 m g / k g per dose administered orally every 6 to 12 hours, appeared to be an effective and safe treatment for resistant hypertension in infants and children. (J PEDIATR1991;118:638-43)
Nitrendipine, a new calcium-channel antagonist, is a substituted 1,4-dihydropyridine derivative with a molecular structure and mechanism of action similar to those of nifedipine.1 Both drugs antagonize transmembrane calcium flux in peripheral vascular smooth muscle, resulting in decreased peripheral vascular resistance and vasodilation.2 Although nifedipine has been used successfully to treat hypertension in children and adutts, 36 its relatively short duration of action has limited its usefulness as a long-term antihypertensive agent in children), 4 In contrast, results of studies in adults have shown nitrendipine to have a longer
duration of action than nifedipine and to reduce blood pressure when administered twice daily. 7 This report details the pharmacokinetic and pharmacodynamic data from a series of 25 children with hypertension treated with nitrendipine for up to 12 weeks.
Supported by National Research Service Award 5 F32 DK0776401, Miles Laboratories. Submitted for publication Aug. 30, 1990; accepted Nov. 16, 1990. Reprint requests: Thomas G. Wells, MD, Arkansas Children's Hospital, 800 Marshall St., Little Rock, AR 72202. 9/25/26568
METHODS
638
AUCss
Clnax K~
Trnax
Area under the plasma concentration versus time curve at steady state Apparent peak serum concentration Elimination rate constant Apparent time at which peak serum concentration occurred
Children participating in this study were patients at the University of Minnesota Hospital and Clinics and were hospitalized for at least 24 hours before and 48 hours after initiation of nitrendipine therapy. Patients were eligible to
Volume 118 Number 4, Part 1
receive nitrendipine if systolic and diastolic blood pressure was persistently above the 95th percentile for age and gender. 8 Patients with congestive heart failure, arrhythmias, or malignancy were excluded from the study. This protocol was approved by the University of Minnesota Committee on the Use of Human Subjects in Research. Written consent for participation was obtained from parents and when appropriate from patients. Study design. Blood pressure and heart rate were measured by means of standard techniques with patients in the supine position. 8 A Dinamap oscillometric blood pressure recorder (Critikon, Inc., Tampa, Fla.) was used in patients less than 2 years of age and during dose titration in several older patients. A standard mercury sphygmomanometer was used in all other children. Blood pressure cuff size was chosen according to published guidelines. 8 Regularly scheduled antihypertensive therapy was not changed unless subjects were receiving nifedipine, which was discontinued before nitrendipine was started. Intravenous vasodilators were not administered during the initial dose titration of nitrendipine. Nitrendipine was supplied in tablet form by Miles, Inc., West Haven, Conn. Tablets were fragmented and suspended in water (10 ml or less) for children unable to swallow whole tablets. All doses of nitrendipine were administered orally with water. A cumulative dose-titration protocol was used. After baseline blood pressure and heart rate were determined, an initial dose of 0.1 mg/kg of nitrendipine was administered. Blood pressure and heart rate measurements were repeated every 15 minutes. If systolic or diastolic pressure remained above the 95th percentile for age 8 3 hours after the first dose, a second dose of nitrendipine, 0.25 mg/kg, was administered. If blood pressure remained above the 95th percentile 3 hours later, a third dose (0.5 mg/kg) was given. Beginning with the ninth patient, the protocol was modified by increasing the initial dose of nitrendipine to 0.25 mg/kg. A single subsequent dose of 0.5 mg/kg was administered to patients who did not respond. The total daily dose of nitrendipine was limited to 3 mg/kg per 24 hours or a maximum of 80 mg in 24 hours. The maintenance dose of nitrendipine was determined by the response of individual patients during dose titration and was administered initially every 12 hours. Changes in the maintenance dose and dosing interval were made at the discretion of the investigators according to changes in blood pressure. In patients with blood pressures persistently above the 95th percentile after 96 hours of therapy, treatment was considered unsuccessful and nitrendipine was discontinued. To assess the long-term effect of nitrendipine on blood pressure and heart rate in children, we obtained measurements after 24 hours and 1, 2, 4, 8, and 12 weeks.
Nitrendipine for hypertension
639
Laboratory procedures.The following laboratory results were obtained from each patient before they entered the study: complete blood cell count, urinalysis, and serum levels of sodium, potassium, chloride, bicarbonate, total and ionized calcium, phosphate, albumin, total protein, glucose, cholesterol, triglycerides, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, uric acid, blood urea nitrogen, and creatinine. An electrocardiogram, chest roentgenogram, and echocardiogram were obtained from each patient. Determinations of serum levels of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, and total and ionized calcium were repeated 24 hours, 7 days, 4 weeks, and 12 weeks after nitrendipine was started. All other tests, with the exception of chest roentgenography, were repeated after 12 weeks or when nitrendipine was discontinued. Glomerular filtration rate was estimated according to the method of Schwartz et al. 9 Analysis of the disposition of nitrendipine was studied in 13 patients on a stable dosing regimen for a minimum of 5 days. Serial blood samples were collected before and 30 minutes and 1, 2, 3, 4, and 6 hours after an oral dose of nitrendipine. Samples were collected at 8 hours from patients with longer dosing intervals. After centrifugation, plasma was removed and stored at - 2 0 ~ C until shipment in dry ice to Miles Laboratories. Nitrendipine concentrations were measured by Dr. George Krol with capillary gas chromatography. 1~ Data analysis. All patient data are expressed as mean ___ SEM. Individual plasma concentration versus time data were evaluated with S I P H A R / B a s e (SIMED, Creteil, France). Initial polyexponential parameter estimates were generated with the use of a peeling algorithm) 1 Final parameter estimates were obtained from a nonlinear, weighted least-squares algorithm with the weight set as the reciprocal of the calculated concentration) 2 Compartment model selection was made after application of Akaike's information criterion. 13 Finally compartment model-dependent pharmacokinetic parameters were calculated by previously described methods) 4 Pharmacokinetic parameters are expressed as mean ___SEM. Differences between pretherapy and posttherapy physiologic measurements and laboratory findings were analyzed with a two-tailed Student t test for paired data with Bonferroni correction. 15 To compare the number of patients who became normotensive after receiving initial doses of either 0.1 or 0.25 mg/kg, a two-tailed Fisher Exact Test was used because fewer than five patients were present in at least one cell of the 2 X 2 contingency tables. 16 Possible relationships between age, renal function, and pharmacokinetic parameters were examined by means of least-squares linear regression. 15 Differences between pharmacokinetic param-
640
Wells and S i n a i k o
The Journal o f Pediatrics April 1991
n= 25
25
25
22
25
21
18
180
140 N
=
Sys BP (mmHg)
o-~
Dias BP (mmHg)
t
]E
120
Blood Pressure (mmHg) 100
80
60
I
I
I
[
I
I
I
Baseline
24 Hrs
1 Wk
2 Wk
4 Wk
8 Wk
12 Wk
Duration of Therapy Figure. Systolic and diastolic blood pressure responses (mean _+ SEM) during long-term therapy with nitrendipine. Asterisk indicates blood pressure significantly lower than baseline (p 0.05 in comparison with the lower dose). Long-term therapy with nitrendipine. On the basis of the results of the dose-titration study, maintenance therapy was started at 0.1 mg/kg per dose in one patient, 0.25 mg/kg per dose in four patients, and 0.5 mg/kg per dose in 20 patients. Nitrendipine initially was administered twice daily. Because of the inadequate duration of the antihypertensive response, the dosing interval was decreased to 8 hours in 19 patients and 6 hours in four. The mean daily doses of nitrendipine during maintenance therapy ranged from 1.33 _+ 0.66 to 1.58 _+ 0.49 mg/kg. Systolic and diastolic blood pressure continued to fall during the first week of therapy and remained significantly
Volume 118 Number 4, Part 1
Nitrendipine for hypertension
Table
Table I Pharmacokinetic parameters
Dose (mg/kg) Cmax (ng/ml) Tmax (hr) AUCss (ng/ml*hr) Kc (hr -1) Elimination half-life (hr)
Patient d a t a
0.56 + 0.04 34.7 _+ 9.1 1.5 - 0.3 86.0 + 19.0 0.28 _+ 0.04 2.5
(0.25-0.74) (7.1-110.8) (0.5-4.0) (13.3-210) (0.11-0.49) (1.4-6.3)
641
II
Pharmacokinetic parameters
Dose (mg/kg) Cmax (ng/ml) Tmax (hr)
AUCss (ng/ml*hr) Kc(hr-1) Elimination half-life (hr)
Fasting (n = 5)
Nonfasting (n = 5)
0.57 _+ 0.05 71 _+ 10 1.0 _+ 0.3 158 _+ 20 0.32 _+ 0.07 2.2 (1.4-6.3)
0.59 + 0.05 13 _+ 3* 2.4 _+ 0.5* 46 _+ 16" 0.33 +_ 0.06 2.1 (1.6-5.1)
*Significantlydifferentfromfastingpatients(a
