The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection

Leeuwen, Remko van; Lange, Joep M. A.; Hussey, Elizabeth K.; Donn, Karl H.; Hall, Susan T.; Harker, A.J.; Jonker, P. G.; Danner, Sven A.

doi:10.1097/00002030-199212000-00008

Cited by 118 publications

(90 citation statements)

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“…The mean CL TB of lamivudine in nonhuman primates was very similar to that reported in humans (16). The CL TB was significantly greater than the glomerular filtration rate (15).…”

Section: Discussionsupporting

confidence: 81%

“…However, in preclinical studies lamivudine appeared to be significantly less cytotoxic to uninfected lymphocytes than did the (ϩ) enantiomer (3). On the basis of the in vitro antiretroviral activity and the relative lack of cytotoxicity of lamivudine, phase I/II clinical trials of this agent with both children and adults have been initiated (5,9,12,16).The cerebrospinal fluid (CSF) penetration of several other pyrimidine dideoxynucleosides, including zidovudine and ddC, has been studied in a nonhuman primate model. These studies suggest that the degree of CSF penetration is dependent upon the nucleobase rather than the structural changes to the sugar moiety.…”

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confidence: 99%

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confidence: 99%

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Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates

Blaney

Daniel

Harker

et al. 1995

Antimicrob Agents Chemother

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2-Deoxy-3-thiacytidine is a dideoxycytidine analog with a sulfur in place of the 3 carbon of the ribose. There are two enantiomeric forms of the compound, both of which inhibit human immunodeficiency virus type 1 and 2 replication in vitro. However, the (؊) enantiomer (lamivudine) appears to be significantly less cytotoxic to uninfected lymphocytes than is the (؉) enantiomer. Lamivudine has entered initial clinical trials, and the present study was designed to describe the pharmacokinetic behavior of this compound in both plasma and cerebrospinal fluid (CSF) of primates. Lamivudine was administered as an intravenous bolus dose of 20 mg/kg to five nonhuman primates, and plasma and CSF (ventricular and lumbar) were sampled at frequent intervals for 24 h after administration. Urine samples were also obtained from two animals. The same dose of the racemate (BCH-189) was administered to one animal. The drug was quantitated in CSF and plasma with a reverse-phase high-pressure liquid chromatography technique. Elimination of lamivudine from plasma was biexponential, with a mean alpha phase half-life of 5.4 min, a mean beta phase half-life of 84 min, and a total clearance of 6.1 liters/h. The total clearance of the same dose of BCH-189 in a single animal was 11.0 liters/h. In two animals from which urine was obtained for 12 h postadministration, 32 and 59% of the drug was recovered unchanged. The deamination product of lamivudine was not detected. The CSF/plasma ratio of lamivudine was significantly higher when the drug was measured in the lumbar CSF (mean, 0.41) than when it was measured in the ventricular CSF (mean, 0.079). The measured CSF/plasma ratio for ventricular CSF is equivalent to that of other dideoxycytidine analogs, confirming the importance of the nucleobase in determining the degree of CSF penetration. The difference in lamivudine exposure in ventricular and lumbar CSF suggests that there is a transport mechanism for efflux of cytidine analogs from ventricular CSF.Lamivudine, the (Ϫ) enantiomer of 2Ј-deoxy-3Ј-thiacytidine, is a dideoxynucleoside analog in which the 3Ј carbon of the ribose of 2Ј,3Ј-dideoxycytidine (ddC) is replaced by a sulfur (Fig. 1). (1). Both the (Ϫ) and (ϩ) enantiomers of 2Ј-deoxy-3Ј-thiacytidine have been shown to inhibit in vitro replication of human immunodeficiency virus types 1 and 2. However, in preclinical studies lamivudine appeared to be significantly less cytotoxic to uninfected lymphocytes than did the (ϩ) enantiomer (3). On the basis of the in vitro antiretroviral activity and the relative lack of cytotoxicity of lamivudine, phase I/II clinical trials of this agent with both children and adults have been initiated (5,9,12,16).The cerebrospinal fluid (CSF) penetration of several other pyrimidine dideoxynucleosides, including zidovudine and ddC, has been studied in a nonhuman primate model. These studies suggest that the degree of CSF penetration is dependent upon the nucleobase rather than the structural changes to the sugar moiety. In the present study, the plasma and CSF ...

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“…The mean CL TB of lamivudine in nonhuman primates was very similar to that reported in humans (16). The CL TB was significantly greater than the glomerular filtration rate (15).…”

Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates

Blaney

Daniel

Harker

et al. 1995

Antimicrob Agents Chemother

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“…Drugs were administered subcutaneously into the backs of animals at a regimen of 8 mg per kg of body weight once daily. The dosage regimen of 3TC was selected because it is expected to give areas under the concentration-time curve for adult macaques similar to those of the daily dose of 3TC used in human pediatric patients (4 mg/kg twice daily) (36,42) or adult patients (150 mg orally twice daily) (24,57), except that for our macaques, it was administered in a single daily dose. Drug dosages were adjusted weekly according to body weight.…”

Section: Methodsmentioning

confidence: 99%

Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

Rompay

Matthews²,

Higgins³

et al. 2002

J Virol

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. The two SIVmac239-184V-infected animals of group C did not receive any drug treatment, and in both animals the virus population reverted to predominantly wild type (184M) by 8 weeks after inoculation. The other five SIVmac239-184V-infected animals (group B) were treated with (؊)-FTC to prevent reversion. Although virus levels 1 week after inoculation were lower in the SIVmac239-184V-infected macaques than in the SIVmac239-infected animals, no significant differences were observed from week 2 onwards. Two animals in each group developed AIDS and were euthanized, while all other animals were clinically stable at 46 weeks of infection. These data demonstrate that the M184V mutation in SIV conferred a slightly reduced fitness but did not affect disease outcome.

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“…524W91 resembles another oxathiolane nucleoside analog, (2R, 5S-)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (3TC; Lamivudine). 3TC is currently undergoing clinical trials as a therapy for infection with HIV (1,23) and HBV (22). Like 3TC, 524W91 is synthesized as part of a racemic mixture of (+) and (-) enantiomers that are analogous to D-and L-nucleosides, respectively (4).…”

mentioning

confidence: 99%

Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus

Frick

Lambe

John

et al. 1994

Antimicrob Agents Chemother

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(2'R, 5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 0.02 liter/kg. The terminal elimination half-life was 1.0 + 0.2 h. The absolute bioavailability after oral dosing was 63% + 4% at 10 mg/kg.Concentrations of 524W91 in the cerebrospinal fluid were 4% 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% + 6% of the radioactive dose in the 0-to 72-h urine, 33% + 10% in the feces, and 10% 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The major urinary metabolite was a 3'-sulfoxide, constituting 27% of the radiolabeled material in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% 7% of the radiolabel in the 0-to 48-h urine. Small amounts of the 3'-sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.

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The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection

Cited by 118 publications

References 0 publications

Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates

Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates

Virulence and Reduced Fitness of Simian Immunodeficiency Virus with the M184V Mutation in Reverse Transcriptase

Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus

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