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Pharmacotherapeutic Group: nucleoside analogue. ATC Code: J05 AF30.
Pharmacology: Pharmacodynamics: Mechanism of Action: Lamivudine and zidovudine are potent, selective inhibitors of HIV-1 and HIV-2. Both active substances are metabolised sequentially by intracellular kinases to the 5'-triphosphate (TP). Lamivudine TP and zidovudine-TP are substrates for and competitive inhibitors of HIV reverse transcriptase. However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine and zidovudine triphosphates show significantly less affinity for host cell DNA polymerases. No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine). No antagonistic effects in vitro were seen with zidovudine and other antiretrovirals (tested agents: abacavir, didanosine, lamivudine, and interferon-alpha).
In vitro, lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in vitro. Lamivudine therefore has, in vitro, a high therapeutic index.
Pharmacodynamic Effects: HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase (RT). This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.
Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine -resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine -resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold decrease in susceptibility to didanosine and zalcitabine; the clinical significance of these findings is unknown.
Resistance to thymidine analogues (of which zidovudine is one) is well characterised and is conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of the six mutations. These thymidine analogue mutations alone do not cause high-level cross-resistance to any of the other nucleosides, allowing for the subsequent use of any of the other approved reverse transcriptase inhibitors.
Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second typically involving a T69S mutation plus a 6-base pair insert at the same position, result in phenotypic resistance to AZT as well as to the other approved nucleoside reverse transcriptase inhibitors. Either of these two patterns of multinucleoside resistance mutations severely limits future therapeutic options.
In clinical studies lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and to increase CD4 cell counts. Clinical end-point data indicate that lamivudine in combination with zidovudine alone or in combination with zidovudine containing treatment regimens results in a significant reduction in the risk of disease progression and mortality.
Individually, lamivudine and zidovudine therapy has resulted in HIV clinical isolates which show reduced sensitivity in vitro to the nucleoside analogue to which they have been exposed. Evidence from clinical studies show that lamivudine plus zidovudine delays the emergence of zidovudine-resistant isolates in individuals with no prior anti-retroviral therapy.
In vitro susceptibility testing has not been standardised and results may vary according to methodological factors. The relationship between in vitro susceptibility of HIV to lamivudine and/or zidovudine and the clinical response to therapy remain under investigation.
Lamivudine and zidovudine have been widely used as components of antiretroviral combination therapy with other antiretroviral agents of the same class (nucleoside reverse transcriptase inhibitors) or different classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).
Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V mutations.
Post-exposure prophylaxis (PEP): Internationally recognised guidelines (Centre for Disease Control and Prevention - June 1998), recommend that in the event of accidental exposure to HIV infected blood e.g. from a needlestick injury, a combination of zidovudine and lamivudine should be administered promptly (within one to two hours). In cases of higher risk of infection a protease inhibitor should be included in the regimen. It is recommended that antiretroviral prophylaxis be continued for four weeks. No controlled clinical studies have been carried out in post-exposure prophylaxis and supporting data is limited. Seroconversion may still occur despite prompt treatment with antiretroviral agents.
Clinical Studies: The Antiretroviral Pregnancy Registry (APR) has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,500 exposures during the first trimester, over 7,200 exposures during the second/third trimester and included 143 and 207 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.1% (2.6, 3.7%) and in the second/third trimester, 2.9% (2.5, 3.3%). The APR has received reports of over 13,000 exposures to zidovudine during pregnancy resulting in live birth. These consist of over 4,100 exposures during the first trimester, over 9,300 exposures during the second/third trimester and included 133 and 264 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.7, 3.8%) and in the second/third trimester, 2.8% (2.5, 3.2%). These proportions are not significantly higher than those reported in the two population based surveillance systems (2.72 per 100 live births and 4.17 per 100 live births respectively). The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine or zidovudine compared to the background rate.
Pharmacokinetics: Absorption: Lamivudine and zidovudine are well absorbed from the gut. The bioavailability of oral lamivudine in adults is normally between 80-85% and for zidovudine 60-70%. A bioequivalence study compared COMBIVIR with 3TC 150 mg and RETROVIR 300 mg tablets taken together. The effect of food on the rate and extent of absorption was also studied. COMBIVIR was shown to be bioequivalent to 3TC 150 mg and RETROVIR 300 mg given as separate tablets, when administered to fasting subjects.
Following COMBIVIR administration, lamivudine and zidovudine Cmax (95% confidence interval) values were 1.5 (1.3-1.8) μg/ml and 1.8 (1.5-2.2) μg/ml, respectively. The median (range) lamivudine and zidovudine tmax values were 0.75 (0.50-2.00) hours and 0.50 (0.25-2.00) hours respectively. The extent (AUC) of lamivudine and zidovudine absorption and estimates of half-life following administration of COMBIVIR with food were similar when compared to fasting subjects, although the rate of absorption (Cmax, tmax) was slowed. Based on these data COMBIVIR may be administered with or without food.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic characteristics of the active ingredient and the in vitro dissolution behaviour of lamivudine-zidovudine tablets in water, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Distribution: Intravenous studies with lamivudine and zidovudine showed that the mean apparent volume of distribution is 1.3 and 1.6 l/kg respectively. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (less than 36% serum albumin in vitro). Zidovudine plasma protein binding is 34% to 38%. Interactions with medicinal products involving binding site displacement are not anticipated with COMBIVIR.
Data show that lamivudine and zidovudine penetrate the central nervous system and reach the cerebrospinal fluid (CSF). The mean ratios of CSF/serum lamivudine and zidovudine concentrations 2-4 hours after oral administration were approximately 0.12 and 0.5, respectively. The true extent of penetration of lamivudine or relationship with any clinical efficacy is unknown.
Metabolism: Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of the unchanged active substance. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%) and low plasma binding.
The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50-80% of the administered dose eliminated by renal excretion. 3'-amino-3'-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous dosing.
Elimination: The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (greater than 70%) via the organic cationic transport system.
From studies with intravenous zidovudine, the mean terminal plasma half- life was 1.1 hours and the mean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be 0.34 l/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys.
Special Patient Populations: Elderly: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.
Children: In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and at all dose levels studied in adults and children, the bioavailability was between 60-74% with a mean of 65%. Cssmax levels were 4.45 μM (1.19 μg/ml) following a dose of 120 mg zidovudine (in solution)/m2 body surface area and 7.7 μM (2.06 μg/ml) at 180 mg/m2 body surface area. Dosages of 180 mg/m2 four times daily in children produced similar systemic exposure (24 hour AUC 40.0 hr μM or 10.7 hr μg/ml) as doses of 200 mg six times daily in adults (40.7 hr μM or 10.9 hr μg/ml).
In six HIV-infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics were evaluated while subjects were receiving 120 mg/m2 zidovudine three times daily and again after switching to 180 mg/m2 twice daily. Systemic exposures (daily AUC and Cmax) in plasma from the twice daily regimen appeared equivalent to those from the same total daily dose given in three divided doses.
In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in paediatric patients below 12 years of age. In addition, systemic clearance values were greater in younger paediatric patients and decreased with age, approaching adult values around 12 years of age. Due to these differences, the recommended dose for lamivudine in children (from three months to 12 years; approximately 6 kg to 40 kg) is 8 mg/kg/day.
This dose will achieve an average AUC0-12 ranging from approximately 3,800 to 5,300 ng.h/ml. Recent findings indicate that exposure in children 2 to < 6 years of age may be reduced by about 30% compared with other age groups. Further data to support this conclusion are currently awaited. At present, the available data do not suggest that lamivudine is less efficacious in this age group.
Renal Impairment: Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction, due to decreased renal clearance. Dose reduction is required for patients with creatinine clearance of less than 50 ml/min. Zidovudine concentrations have also been shown to be increased in patients with advanced renal failure.
Hepatic Impairment: Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage adjustment of zidovudine may be necessary in patients with severe hepatic impairment.
Pregnancy: The pharmacokinetics of lamivudine and zidovudine were similar to that of non-pregnant adults. In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery. Zidovudine was measured in plasma and gave similar results to those observed for lamivudine.
Toxicology: Pre-clinical Safety Data: No synergy of toxicity has been observed in studies with lamivudine in combination with zidovudine. The clinically relevant effects of the two medicinal products in combination are anaemia, neutropenia and leucopenia.
Carcinogenesis, mutagenesis: In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.
In oral carcinogenicity studies with zidovudine in mice and rats, late appearing-vaginal epithelial tumours were observed. There were no other zidovudine-related tumours observed in either sex of either species. A subsequent intravaginal carcinogenicity study confirmed the hypothesis that the vaginal tumours were the result of long term local exposure of the rodent vaginal epithelium to high concentrations of unmetabolised zidovudine in urine. The predictive value of rodent carcinogenicity studies for humans is uncertain and thus the clinical significance of these findings is unclear.
In addition, two transplacental carcinogenicity studies have been conducted in mice. In one study, by the US National Cancer Institute, zidovudine was administered at maximum tolerated doses to pregnant mice from day 12 to 18 of gestation. One year post-natally, there was an increase in the incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the highest dose level (420mg/kg/term body weight).
In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with exposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in the standard oral carcinogenicity study. The second study thus provided no evidence that zidovudine acts as a transplacental carcinogen.
It is concluded that the transplacental carcinogenicity data from the first study represents a hypothetical risk, whereas the reduction in risk of maternal transfection of HIV to the uninfected child by the use of zidovudine in pregnancy has been well proven.
Neither lamivudine nor zidovudine are mutagenic in bacterial tests, but like many nucleoside analogues they show activity in in vitro mammalian tests such as the mouse lymphoma assay. Lamivudine has not shown any genotoxic activity in in vivo studies at doses that gave plasma concentrations up to 40 to 50 times higher than clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.
Zidovudine showed clastogenic effects in an oral repeated dose micronucleus test in mice. Peripheral blood lymphocytes from AIDS patients receiving zidovudine treatment have also been observed to contain higher numbers of chromosome breakages. A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood leukocytes of infants from zidovudine-treated mothers. The clinical implications of these findings are unknown.
Reproductive toxicology: In reproductive studies in animals both lamivudine and zidovudine were shown to cross the placenta, this has also been confirmed in humans. Lamivudine has demonstrated evidence of causing an increase in early embryonic deaths in the rabbit at relatively low systemic exposures, comparable to those achieved in man, but not in the rat even at very high systemic exposure. Zidovudine had a similar effect in both species, but only at very high systemic exposures.
Lamivudine was not teratogenic in animal studies. At maternally toxic doses, zidovudine given to rats during organogenesis resulted in an increased incidence of malformations, but no evidence of foetal abnormalities was observed at lower doses.
Neither zidovudine nor lamivudine have shown evidence of impairment of fertility in studies in male and female rats.
