Nevirapine clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics

### Adults
The single-dose pharmacokinetics of VIRAMUNE XR was studied in 17 healthy volunteers. Nevirapine was absorbed with a median tmax of approximately 24 hrs. The mean Cmax and AUC0- of nevirapine were 2060 ng per mL and 161,000 ng*hr/mL, respectively. The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg of immediate-release VIRAMUNE, was approximately 75%.
The multiple-dose pharmacokinetics of VIRAMUNE XR was studied in 24 HIV-1 infected subjects who switched from chronic VIRAMUNE IR to VIRAMUNE XR. The mean nevirapine AUC0-24,ss and Cmin,ss after 19 days of VIRAMUNE XR dosing under fasted conditions were 82,000 ng*hr/mL and 2920 ng per mL, respectively. When VIRAMUNE XR was administered under fed conditions, the mean nevirapine AUC0-24,ss and Cmin,ss were 96,700 ng*hr/mL and 3150 ng per mL, respectively. The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg of immediate-release VIRAMUNE, under fasted and fed conditions, was 80% and 94%, respectively. The difference in the bioavailability of nevirapine, when VIRAMUNE XR is dosed under fasted or fed conditions, is not considered clinically relevant. VIRAMUNE XR can be taken with or without food.
In single-dose, parallel-group bioavailability trial (1100.1517) in adults, the VIRAMUNE XR 100 mg tablet exhibited extended-release characteristics of prolonged absorption and lower maximal concentration, as compared to the immediate-release VIRAMUNE 200 mg tablet.
Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21  0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk . Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg per mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.
In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady state with immediate-release VIRAMUNE 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4  10.5% of the radiolabeled dose was recovered, with urine (81.3  11.1%) representing the primary route of excretion compared to feces (10.1  1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.
Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg per day of immediate-release VIRAMUNE. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg per day.

### Specific Populations
HIV-1 seronegative adults with mild (CrCL 50-79 mL per min; n=7), moderate (CrCL 30-49 mL per min; n=6), or severe (CrCL less than 30 mL per min; n=4) renal impairment received a single 200 mg dose of immediate-release VIRAMUNE in a pharmacokinetic trial. These subjects did not require dialysis. The trial included six additional subjects with renal failure requiring dialysis.
In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose of immediate-release VIRAMUNE following each dialysis treatment is indicated . VIRAMUNE XR has not been studied in patients with renal dysfunction.
In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity . The subjects studied were receiving antiretroviral therapy containing immediate-release VIRAMUNE 200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.
In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of immediate-release VIRAMUNE, a significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.
Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment . VIRAMUNE XR has not been evaluated in patients with hepatic impairment.
In the multinational 2NN trial of immediate-release VIRAMUNE, a population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of gender cannot solely be explained by body size.
The effects of gender on the pharmacokinetics of VIRAMUNE XR have been investigated in Trial 1100.1486. Female subjects tend to have higher (approximately 20 - 30%) trough concentrations in both VIRAMUNE XR and immediate-release VIRAMUNE treatment groups.
An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg per mL Black, 3.8 mcg per mL Hispanic, 4.3 mcg per mL Caucasian) with long-term treatment with immediate-release VIRAMUNE at 400 mg per day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.
Black subjects (n=80/group) in Trial 1100.1486 showed approximately 30 to 35% higher trough concentrations than Caucasian subjects (250-325 subjects/group) in both immediate-release VIRAMUNE and VIRAMUNE XR treatment groups over 96 weeks of treatment at 400 mg per day.
Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 1868 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years .
The pharmacokinetics of VIRAMUNE XR were assessed in HIV-1 infected children 3 to less than 18 years of age. Children enrolled received weight or body surface area dose-adjusted immediate-release VIRAMUNE in combination with other antiretrovirals for a minimum of 18 weeks and then were switched to VIRAMUNE XR tablets in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined.
Overall, the mean systemic nevirapine exposures in children 6 to less than 18 years of age following administration of VIRAMUNE XR and immediate-release VIRAMUNE were similar. Based on intensive PK data (N=17), the observed geometric mean ratios of VIRAMUNE XR to immediate-release VIRAMUNE were approximately 97% for Cmin,ss and 94% for AUCsswith 90% confidence intervals within 80% - 125%; the ratio for Cmax,ss was lower and consistent with a once daily extended-release dosage form.
Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than 6 years of age to support the use of VIRAMUNE XR in this age group.