12.3 PharmacokineticsThe pharmacoki

12.3 Pharmacokinetics
The pharmacokinetics of EPANED Oral Solution were shown to be similar to that of Vasotec tablets
under fasted conditions. A high-fat meal reduced the C of enalapril and enalaprilat by 46% and 36%,
respectively. The exposure, as measured by AUC, to enalaprilat was reduced by 23%. The time to peak
concentrations (C ) was delayed by 20 minutes for enalapril and 62 minutes for enalaprilat. The
trough plasma concentrations of enalapril (from 6 to 12 hours) and enalaprilat (from 16 to 36 hours) are
similar between fasted and fed administrations.
Adults
Following oral administration of enalapril maleate tablets, peak serum concentrations of enalapril occur
within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately
60%. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract.
Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensinconverting
enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally.
Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril
maleate. Excretion of enalapril is primarily renal.
Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or enalapril. The
principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril.
There is no evidence of metabolites of enalapril, other than enalaprilat.
The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently
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representing a small fraction of the administered dose that has been bound to ACE. The amount bound
does not increase with dose, indicating a saturable site of binding. The effective half-life for
accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.
The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in
patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With
glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak
concentration increases, and time to steady state may be delayed. The effective half-life of enalaprilat
following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency [see
Dosage and Administration (2.1)]. Enalaprilat is dialyzable at the rate of 62 mL/min.
Pediatric Patients
A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric
patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril
maleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and
the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administered
dose. Conversion of enalapril to enalaprilat was in the range of 63-76%. The overall results of this
study indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to ≤16 years
are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy
adults.
In the above pediatric study, enalapril maleate was given as tablets and for those children and infants
who were unable to swallow tablets or who required a lower dose than is available in tablet form,
enalapril was administered in a suspension formulation.
Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does
not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any
tissues. Milk of lactating rats contains radioactivity following administration of C-enalapril maleate.
Radioactivity was found to cross the placenta following administration of labeled drug to pregnant
hamsters.

Hasil (Bahasa Indonesia) 1:

12.3 farmakokinetikPharmacokinetics dari solusi lisan EPANED sudah terbukti mirip dengan Vasotec tabletdalam kondisi berpuasa. Makanan tinggi lemak berkurang C enalapril dan enalaprilat dengan 46%, 36%,masing-masing. Eksposur, yang diukur dengan AUC, untuk enalaprilat berkurang sebesar 23%. Waktu untuk puncakkonsentrasi (C) ditunda oleh 20 menit untuk enalapril dan 62 menit untuk enalaprilat. TheKadar plasma palung enalapril (dari 6 hingga 12 jam) dan enalaprilat (dari 16 hingga 36 jam) adalahserupa antara administrasi berpuasa dan diberi makan.Orang dewasaSetelah pemberian oral enalapril maleate tablet, konsentrasi serum puncak enalapril terjadidalam waktu sekitar satu jam. Berdasarkan kemih pemulihan, tingkat penyerapan enalapril adalah sekitar60%. Enalapril penyerapan tidak dipengaruhi oleh kehadiran makanan dalam saluran pencernaan.Setelah penyerapan, enalapril adalah dihidrolisis untuk enalaprilat, yang merupakan angiotensinconverting lebih kuatinhibitor enzim dari enalapril; enalaprilat kurang diserap ketika diberikan secara oral.Konsentrasi serum puncak enalaprilat terjadi tiga sampai empat jam setelah oral dosis enalaprilmaleate. Ekskresi enalapril terutama ginjal.Sekitar 94% dari dosis pulih kencing dan tinja sebagai enalaprilat atau enalapril. Thekomponen utama dalam urin yang enalaprilat, akuntansi untuk sekitar 40% dari dosis dan enalapril utuh.There is no evidence of metabolites of enalapril, other than enalaprilat.The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently®maxmaxrepresenting a small fraction of the administered dose that has been bound to ACE. The amount bounddoes not increase with dose, indicating a saturable site of binding. The effective half-life foraccumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that inpatients with normal renal function until the glomerular filtration rate is 30 mL/min or less. Withglomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peakconcentration increases, and time to steady state may be delayed. The effective half-life of enalaprilatfollowing multiple doses of enalapril maleate is prolonged at this level of renal insufficiency [seeDosage and Administration (2.1)]. Enalaprilat is dialyzable at the rate of 62 mL/min.Pediatric PatientsA multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatricpatients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalaprilmaleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours andthe mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administereddose. Conversion of enalapril to enalaprilat was in the range of 63-76%. The overall results of thisstudy indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to ≤16 yearsare consistent across the studied age groups and consistent with pharmacokinetic historic data in healthyadults.In the above pediatric study, enalapril maleate was given as tablets and for those children and infantswho were unable to swallow tablets or who required a lower dose than is available in tablet form,enalapril was administered in a suspension formulation.Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat doesnot enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in anytissues. Milk of lactating rats contains radioactivity following administration of C-enalapril maleate.Radioactivity was found to cross the placenta following administration of labeled drug to pregnanthamsters.