Combivir

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults

COMBIVIR: One COMBIVIR Tablet was bioequivalent to one EPIVIR Tablet (150mg) plus one RETROVIR Tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

Lamivudine: The pharmacokinetic properties of lamivudine in fasting patients are summarized in Table 1. Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine: The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is 3’-azido-3'-deoxy-5’-O-b-D-glucopyranuronosylthymidme (GZDV). GZDV area under the curve (AUC) is about three-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3’-amino-3’-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

Table1: Pharmacokinetic Parameters* for Lamivudine and Zidovudine in Adults

Parameter	Lamivudine		Zidovudine
Oral bioavailability (%)	86 ± 16	n = 12	64 ± 10	n = 5
Apparent volume of distribution (L/kg)	1.3 ± 0.4	n = 20	1.6 ± 0.6	n = 8
Plasma protein binding (%)	<36		<38
CSF: plasma ratio^**	0.12 [0.04 to 0.47]	n = 38^†	0.60 [0.04 to 2.62]	n = 39^‡
Systemic clearance (L/h/kg)	0.33 ± 0.06	n = 20	1.6 ± 0.6	n = 6
Renal clearance (L/h/kg)	0.22 ± 0.06	n = 20	0.34 ± 0.05	n = 9
Elimination half-life(h)^§	5 to 7		0.5 to 3

Effect of Food on Absorption of COMBIVIR

COMBIVIR may be administered with or without food. The extent of lamivudine and zidovudine absorption (AUC) following administration of COMBIVIR with food was similar when compared to fasting healthy subjects (n = 24).

Special Populations

Impaired Renal Function

COMBIVIR: Because lamivudine and zidovudine require dose adjustment in the presence of renal insufficiency, COMBIVIR is not recommended for patients with impaired renal function (see PRECAUTIONS).

Impaired Hepatic Function

COMBIVIR: A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. Because COMBIVIR is a fixed-dose combination that cannot be adjusted for this patient population, COMBIVIR is not recommended for patients with impaired hepatic function.

Pregnancy

See PRECAUTIONS: Pregnancy.

COMBIVIR: No data are available.

Zidovudine: Zidovudine pharmacokinetics has been studied in a Phase 1 study of eight women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter zidovudine pharmacokinetics. In a nonpregnant adult population, a potential for interaction has been identified (see Drug Interactions below).

Nursing Mothers

See PRECAUTIONS: Nursing Mothers.

COMBIVIR: No data are available.

Zidovudine: After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum.

Pediatric Patients

COMBIVIR: COMBIVIR should not be administered to pediatric patients less than 12 years of age because it is a fixed-dose combination that cannot be adjusted for this patient population.

Geriatric Patients

Lamivudine and zidovudine pharmacokinetics have not been studied in patients over 65 years of age.

Gender

COMBIVIR: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine exposure (AUC¥) or lamivudine AUC¥ normalized for body weight.

Race: Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions

See DRUG INTERACTIONS section.

COMBIVIR: No drug interaction studies have been conducted using COMBIVIR Tablets.

Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 h).

Table 2: Effect of Coadministered Drugs on Lamivudine and Zidovudine AUC*

Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.

Drugs That May Alter Lamivudine Blood Concentrations
Coadministered Drug and Dose	Lamivudine Dose	n	Lamivudine Concentrations		Concentration of Coadministered Drug
Coadministered Drug and Dose	Lamivudine Dose	n	AUC	Variability	Concentration of Coadministered Drug
Nelfinavir 750 mg q 8 hr x 7 to 10 days	single 150 mg	11	AUC 10%	95% CI: 1% to 20%	«
Trimethoprim160mg/ Sulfamethoxazole 800 mg daily x 5 days	single 300 mg	14	AUC 43%	90% CI: 32% to 55%	«
Atovaquone 750 mg q12h with food	200 mg q8h	14	AUC 31%	Range 23% to78%**	«
Fluconazole 400 mg daily	200 mg q8h	12	AUC 74%	95% CI: 54% to 98%	Not Reported
Methadone 30 to 90 mg daily	200 mg q4h	9	AUC 43%	Range 16% to 64%**	«
Nelfinavir 750 mg q8hr x 7 to 10 days	single 200 mg	11	¯ AUC 35%	Range 28% to 41%	«
Probenecid 500 mg q6h x 2 days	2 mg/kg q8h x 3 days	3	AUC 106%	Range 100% to 170%**	Not Assessed
Ritonavir 300 mg q6h x 4 days	200 mg q8h x 4 days	9	¯ AUC 25%	95% CI: 15% to 34%	«
Valproic acid 250 mg or 500 mg q8h x 4 days	100 mg q8h x 4 days	6	AUC 80%	Range 64% to 130%**	Not Assessed

MICROBIOLOGY

Mechanism of Action

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). The principal mode of action of L-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue. L-TP is a weak inhibitor of mammalian DNA polymerases a and b, and mitochondrial DNA polymerase-g.

Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5’-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleoside analogue. ZDV-TP is a weak inhibitor of the mammalian DNA polymerase-a and mitochondrial DNA polymerase-g and has been reported to be incorporated into the DNA of cells in culture.

Antiviral Activity In Vitro

The relationship between in vitro susceptibility of HIV to lamivudine or zidovudine and the inhibition of HIV replication in humans has not been established.

Lamivudine Plus Zidovudine: In HIV-1—infected MT-4 cells, lamivudine in combination with zidovudine had synergistic antiretroviral activity. Synergistic activity of lamivudine and zidovudine was also shown in a variable-ratio study.

Lamivudine: In vitro activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). IC50 and IC90 values (50% and 90% inhibitory concentrations) for lamivudine were 0.0006 mcg/mL to 0.034 mcg/mL and 0.015 to 0.321 mcg/mL, respectively. Lamivudine had anti—HIV-1 activity in all acute virus-cell infections tested.

Zidovudine: In vitro activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The IC50 and IC90 values for zidovudine were 0.003 to 0.013 mcg/mL and 0.03 to 0.13 mcg/mL, respectively. Zidovudine had anti—HIV-1 activity in all acute virus-cell infections tested. However, zidovudine activity was substantially less in chronically infected cell lines. In cell culture drug combination studies with zidovudine, interferon-alpha demonstrated additive activity and zalcitabine, didanosine, saquinavir, indinavir, ritonavir, nelfinavir, nevirapine, and delavirdine demonstrated synergistic activity.

Drug Resistance

Lamivudine Plus Zidovudine Administered As Separate Formulations: In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple mutations, the most essential of which may be at codon 333 (Gly®Glu). The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.

Lamivudine: Lamivudine- resistant solates of HIV-1 have been selected in vitro and have also been recovered from patients treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of the resistant isolates showed that the resistance was due to mutations in the HIV-1 reverse transcriptase gene at codon 184 from methionine to either isoleucine or valine.

Zidovudine: HIV isolates with reduced susceptibility to zidovudine have been selected in vitro and were also recovered from patients treated with zidovudine. Genotypic analyses of the isolates showed mutations which result in five amino acid substitutions (Met41®Leu, Asp67®Asn, Lys70®Arg, Thr215®Tyr or Phe, and Lys219®Gln) in the HIV-1 reverse transcriptase gene. In general, higher levels of resistance were associated with greater number of mutations.

Cross-Resistance

Cross-resistance among certain reverse transcriptase inhibitors has been recognized.

Lamivudine Plus Zidovudine: Cross-resistance between lamivudine and zidovudine has not been reported. In some patients treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a mutation at codon 184 which confers resistance to lamivudine. In the presence of the 184 mutation, cross-resistance to didanosine and zalcitabine has been seen in some patients; the clinical significance is unknown. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple drugs, including lamivudine, have emerged (see under Zidovudine below).

Lamivudine: See Lamivudine Plus Zidovudine (above).

Zidovudine: HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients treated for ³1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of genotypic resistant mutations with such combination therapies was different (Ala62®Val, Val75®Ile, Phe77®Leu, Phel 16®Tyr, and Gln151®Met) from the pattern with zidovudine monotherapy, with the 151 mutation being most commonly associated with multidrug resistance. The mutation at codon 151 in combination with the mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine.

Multiple drug resistance has been observed in two of 39 (5%) patients receiving zidovudine and didanosine combination therapy for 2 years.

CLINICAL STUDIES

COMBIVIR: There have been no clinical trials conducted with COMBIVIR. One COMBIVIR Tablet given twice a day is an alternative regimen to EPIVIR Tablets 150 mg twice a day plus RETROVIR 600 mg per day in divided doses.

Lamivudine Plus Zidovudine: The NUCB3007 (CAESAR) study was conducted using EPIVIR 150 mg Tablets (150 mg b.i.d.) and RETROVIR 100 mg Capsules (2 x 100 mg t.i.d.). CAESAR was a multicenter, double-blind, placebo-controlled study comparing continued current therapy [zidovudine alone (62% of patients) or zidovudine with didanosine or zalcitabine (38% of patients)] to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. A total of 1,816 HIV-infected adults with 25 to 250 (median 122) CD4 cells/mm3 at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on study was 12 months. Results are summarized in Table 3.

Table 3: Number of Patients (%) With At Least One HIV Disease-Progression Event or Death

Endpoint	Current Therapy (n = 460)	EPIVIR plus Current Therapy (n = 896)	EPIVIR plus a NNRTI* plus Current Therapy (n = 460)
HIV progression or death	90 (19.6%)	86 (9.6%)	41 (8.9%)
Death	27 (5.9%)	23 (2.6%)	14 (3.0%)

* An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

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