Development of a Population Simulation Model for HIV Monotherapy Virological Outcomes Using Lamivudine

Hurwitz, Selwyn J.; Asif, Ghazia; Schinazi, Raymond F.

doi:10.1177/095632020701800605

Cited by 10 publications

(13 citation statements)

References 53 publications

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“…NRTIs like tenofovir exert their effects through their intracellular phosphorylated moieties, which are often non-linearly related to plasma pro-drug concentrations [15], [17], [46]. As a consequence, plasma pro-drug concentrations may poorly predict pharmacological activity [47], [48].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, for establishing the link between dose and response, the link between plasma- and intracellular pharmacokinetics is essential, and can subsequently be used to predict the effect of drug administration on virus dynamics. This complete PK-PD link for NRTIs has only rarely been achieved [17]. For TDF, no in silico model exists to the authors’ knowledge, which integrates dosing, pharmacokinetics and antiviral response.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir and Prophylactic Efficacy against HIV-1 Infection

2012

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Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration can protect healthy individuals from HIV-1 infection. While PrEP was recently approved by the FDA, the potential long-term consequences of PrEP implementation remain entirely unclear. The aim of this study is to predict the efficacy of different prophylactic strategies with the pro-drug tenofovir-disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and mode of TDF administration (daily- vs. single dose), adherence and the number of transmitted viruses. We developed a pharmacokinetic model for TDF and its active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics were coupled to an HIV model and viral decay following TDF mono-therapy was predicted, consistent with available data. Subsequently, a stochastic approach was used to estimate the % infections prevented by (i) daily TDF-based PrEP, (ii) one week TDF started either shortly before, or -after viral exposure and (iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical solutions were derived to assess the relation between intracellular TFV-DP concentrations and prophylactic efficacy. The predicted efficacy of TDF was limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP half-life and decreased with increasing numbers of transmitted viruses. Once daily TDF-based PrEP yielded 80% protection, if at least 40% of pills were taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent 50% infections, when given at least before virus exposure. The efficacy dropped to 10%, when given 1 h before 24 h exposure. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. The use of drugs that accumulate more rapidly, or local application of tenofovir gel may overcome the need for drug administration long before virus exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir and Prophylactic Efficacy against HIV-1 Infection

2012

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“…Rosario et al recently utilized clinical trial simulations to streamline the phase 2a development of the CCR5 receptor blocking agent maraviroc (75). Furthermore, Hurwitz et al recently developed a pharmacodynamic model of viral depletion for use with lamivudine (46).…”

Section: Discussionmentioning

confidence: 99%

“…ϩ PBM cells may be useful for possible incorporation into a virus pharmacokineticpharmacodynamic model that relates virus depletion profiles versus time and dose of administration (46,47).…”

Section: Discussionmentioning

confidence: 99%

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

Hurwitz

Asif

Kivel³

et al. 2008

Antimicrob Agents Chemother

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In vitro selection studies and data from large genotype databases from clinical studies have demonstrated that tenofovir disoproxil fumarate and abacavir sulfate select for the K65R mutation in the human immunodeficiency virus type 1 polymerase region. Furthermore, other novel non-thymine nucleoside reverse transcriptase (RT) inhibitors also select for this mutation in vitro. Studies performed in vitro and in humans suggest that viruses containing the K65R mutation remained susceptible to zidovudine (ZDV) and other thymine nucleoside antiretroviral agents. Therefore, ZDV could be coformulated with these agents as a "resistance repellent" agent for the K65R mutation. The approved ZDV oral dose is 300 mg twice a day (b.i.

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“…Once reverse transcription is complete and viral DNA has integrated into host cell DNA, the NAI-TP has no further effect on HIV-1 replication in that cell. The net effect is to block new infections of CD4 þ cells, so that the maximal decline rate in plasma HIV-1 reflects the death rate of infected CD4 þ lymphocytes [7,8]. In contrast, HBV and HCV do not have preintegration reverse transcriptase steps, and NAI-TP directly inhibit the viral replication in infected cells.…”

Section: Introductionmentioning

confidence: 94%

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

Hurwitz

Schinazi

2013

Current Opinion in HIV and AIDS

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Prodrug strategies can address the issues of poor oral bioavailability and delivery of active metabolites to the targeted cells. Additionally, NAPs demonstrate potential for improving deficiencies in oral absorption, metabolism, tissue distribution, cellular accumulation, phosphorylation, and overall potency, in addition to diminishing potential for in-vivo selection of resistant viruses. NAPs continue to be the backbone for the treatment of HIV and HBV, herpesviruses, and adenovirus infections because their active forms are potent, have long intracellular half-lives and are relatively safe with high barrier to resistance.

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Development of a Population Simulation Model for HIV Monotherapy Virological Outcomes Using Lamivudine

Cited by 10 publications

References 53 publications

Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir and Prophylactic Efficacy against HIV-1 Infection

Pharmacokinetics and Pharmacodynamics of the Reverse Transcriptase Inhibitor Tenofovir and Prophylactic Efficacy against HIV-1 Infection

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

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