Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects

Weller, S; Radomski, Kristine M.; Lou, Yu; Stein, Daniel S.

doi:10.1128/aac.44.8.2052-2060.2000

Cited by 69 publications

(58 citation statements)

References 17 publications

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“…Exposure parameters such as C min and C max were also similar regardless of abacavir use ( Table 1). The pharmacokinetic parameters reported in this study are similar to those reported in prior studies of abacavir (4,14,15,17,19,20,25,26 Administration of indinavir less frequently but at a higher dose was expected to result in a higher C max and a lower C min . Indeed, indinavir at 1,200 mg q12h compared to indinavir at 1,000 mg q8h showed a trend toward a higher median C max (15,250 versus 10,172 nM) and a lower median C min (88.1 versus 139.3 nM).…”

Section: Discussionsupporting

confidence: 77%

Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects

DiCenzo

Forrest

Squires

et al. 2003

Antimicrob Agents Chemother

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Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (C min ) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median C min for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P ‫؍‬ 0.19). Compared to the minimum C min range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the C min for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P ‫؍‬ 0.28), apparent volume of distribution at steady state (V ss /F) (P ‫؍‬ 0.25), and half-life (t 1/2 ) (P ‫؍‬ 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (C max s) were 8,968 nM (IR, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P ‫؍‬ 0.66), and the C min s were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P ‫؍‬ 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P ‫؍‬ 0.62), V ss /F (P ‫؍‬ 0.33), and t 1/2 (P ‫؍‬ 0.37) were similar regardless of the dosing regimen. The median C max , C min , CL/F, V ss /F, and t 1/2 for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h.Combination therapy with antiretroviral agents is recommended as routine clinical care for human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals with access to nucleoside analog reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors on the basis of clinical presentation, the plasma HIV RNA concentration, and CD4 ϩ -cell count. However, the optimal use of these different drug classes during chronic combination therapy is dependent on an awareness of potential drug-drug interactions that may alter the pharmacokinetic disposition of one or more components of the regimen.At the time that Adult AIDS Clinical Trials Group (AACTG) Protocol 368 was designed, there were additional areas of pharmacologic interest because (i) pharmacokinetic data describing the metabolic interaction between...

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Section: Discussionsupporting

confidence: 77%

Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects

DiCenzo

Forrest

Squires

et al. 2003

Antimicrob Agents Chemother

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“…Unlike the other nucleoside reverse transcriptase inhibitors, in which the relationship between plasma concentrations and efficacy and/or toxicity is unclear, the AUC of abacavir has been correlated significantly with efficacy [9]. The recommended dose is 8 mg kg -1 twice daily (up to a maximum of 300 mg twice daily) in children aged from 3 months to 16 years, but as shown in the PENTA 15 trial, large interindividual variability in plasma drug concentrations is observed, with AUC0-24 ranging from 4.93 to 22.03 mg h ml -1 [11].…”

Section: Figurementioning

confidence: 99%

“…Numerous papers have suggested children as a target population for antiretrovirals [6][7][8]. For abacavir, a pharmacokineticpharmacodynamic study in adults demonstrated that the endpoint for efficacy, as indicated by the change from baseline in viral load (plasma HIV-1 RNA) and rise in CD4+ T cell count, was significantly correlated with area under the concentration-time curve (AUC) [9]. Given the mechanism of action of abacavir, the exposure-effect relationship can be assumed to be independent of age.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Zhao

Cella

Pasqua

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily. • Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children. WHAT THIS STUDY ADDS • A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. • Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. • A maximum a posteriori probability Bayesian estimator of AUC0–t based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration–time curve (AUC) targeted individualized therapy in infants and toddlers. AIMS To develop a population pharmacokinetic model for abacavir in HIV‐infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed‐effects modelling (NONMEM) software. A two‐compartment model with first‐order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross‐validation and simulation–estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h−1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV‐infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0–t was developed from the final model and can be used routinely to optimize individual dosing.

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“…A two-compartment physiologic model with firstorder absorption and elimination was used to fit the data (9,13,15). A "bioavailability fraction" corresponding to the AUC CSF /AUC plasma ratio was estimated for the population.…”

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confidence: 99%

Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

Capparelli

Letendre

Ellis

et al. 2005

Antimicrob Agents Chemother

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The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.Nucleoside reverse transcriptase inhibitors, in combination with potent nonnucleoside reverse transcriptase inhibitors or protease inhibitors, can decrease viral replication, improve immune function, and prolong survival. Combination antiretroviral regimens may also reduce viral replication in the central nervous system (CNS). Nucleosides appear to penetrate into the CNS better than protease inhibitors and have been useful in treating patients with human immunodeficiency virus (HIV)-associated dementia (5, 12). Many of these agents are substrates for active transporter systems that effectively pump drugs out of the CNS. Cerebrospinal fluid (CSF) and plasma exhibit different viral dynamics, indicating that the CNS may serve as an independent reservoir for HIV replication (4, 6). Optimal antiretroviral concentrations in the CNS are necessary to limit local HIV replication and prevent the development of drug-resistant virus and overall treatment failure (11). A few pharmacokinetic evaluations of abacavir in primates and humans have reported limited penetration into the CNS, as characterized by CSF/plasma ratios, ranging from less than 20% to 35% (3, 8). However, most of these evaluations were derived from measurements collected early in the dose interval, which may have biased the estimates of CSF penetration (4, 5, 7). The CSF/plasma concentration ratio is a dynamic measure, and single measurements may not accurately estimate exposure in this potential sanctuary. The ratio of the areas under the CSF and plasma concentration-time curves (AUC CSF / AUC plasma ) is a better estimate of drug exposure, as it accounts for the variability over the entire dosing interval, thus giving a more accurate estimate of CNS penetration (2, 10). Since multiple CSF samples for individual AUC determinations are difficult to collect, we used sparse CSF and plasma concentrations with population pharmacokinetic analysis to estimate the population abacavir AUC CSF /AUC plasma ratio in HIV-infected patients.Plasma and CSF samples were obtained from 54 male adult HIV-infected patients receiving an abacavir-containing regimen. All subjects were consenting participants in prospective research studies conducted at the University of California San Diego HIV Neurobehavioral Research Center and approved by the University of California San Diego Institutional Review Board. Fifty-one subjects (94%) were taking abacavir according to a conventional dosing schedule, (300 mg twice daily), while three received 150 mg, 400 mg, or 600 mg twice daily, respectively. All patients were at steady state and free of opportunistic infection at the time of sample colle...

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Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects

Cited by 69 publications

References 17 publications

Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects

Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

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