Application and Impact of Population Pharmacokinetics in the Assessment of Antiretroviral Pharmacotherapy

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Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following singleand multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.Drug-drug interaction studies are an important aspect of clinical pharmacology research and can be a critical step to optimize the use of selected medicines. In the treatment of human immunodeficiency virus (HIV) infection and HIV complications, polypharmacy is compulsory, and this necessitates the conduct of numerous interaction studies (3). Interpretation of results from interaction studies may be challenging when multiple enzyme inducers or inhibitors are involved while study duration is restricted. In some cases, it may be difficult to know when steady state is achieved or only a "pseudo"-steady state may be achievable during a controlled study period.Enzyme induction has important clinical implications when enhanced drug metabolism results in lower drug concentrations, which leads to a suboptimal efficacious response or, even worse, the development of drug resistance. Enzyme induction can be due to (i) a drug affecting its own metabolism (autoinduction), (ii) comedication(s) with induction capability, or (iii) both, such as the concomitant use of efavirenz and carbamazepine.Efavirenz is a potent nonnucleoside reverse transcriptase inhibitor approved for the treatment of HIV-1 infection in combination with other antiretroviral agents (efavirenz [Sustiva] package insert for capsules and tablets; Bristol-Myers Squibb Co., Princeton, NJ) (1). It is metabolized mainly by cytochrome P450 2B6 (CYP2B6) and possibly CYP3A4 or other CYP isoforms to a less extent (efavirenz package insert for capsules and tablets; Bristol-Myers Squibb Co.) (1, 29). Thus, drugs that induce CYP2B6/3A4 (e.g., rifampin, carbamazepine, and phenobarbital) may increase the clearance of efavirenz, resulting...

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confidence: 99%

“…Application of modeling and simulation to the characteriza-tion of enzyme induction have emerged over the years (2,3,23,24,33) as effective means to improve our understanding of the temporal pattern and magnitude of induction. With this approach, enzyme induction can be quantified with data collected prior to steady state.…”

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confidence: 99%

Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine

Zhu

Kaul

Nandy

et al. 2009

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“…This strategy also permits the identification of the sources of variability able to explain interpatient differences, a key factor in this kind of drug therapy; demographics, gene expression, clinical status, and concomitant therapy are the main factors to be investigated. In this sense, population PK modeling has become a valuable tool for identifying and quantifying variability in the exposure to antiretrovirals (5).…”

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confidence: 99%

Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients

Cabrera

Santos

Valverde

et al. 2009

A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n ‫؍‬ 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.

“…Population pharmacokinetics is receiving increasing acceptance for exploration and definition of relevant sources of variation in drug exposure and responses (1). We used it to assess the relative contributions of ritonavir and atazanavir coadministration (2,5,14), of demographic factors, and of the pharmaceutical formulation (9) to the modulation of plasma saquinavir concentrations.…”

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confidence: 99%

Cytochrome P450 3A Inhibition by Atazanavir and Ritonavir, but Not Demography or Drug Formulation, Influences Saquinavir Population Pharmacokinetics in Human Immunodeficiency Virus Type 1-Infected Adults

Hentig

Lötsch

2009

Inadequate concentrations of the human immunodeficiency virus (HIV) protease inhibitor saquinavir jeopardize individual therapy success or produce side effects despite treatment according to the current guidelines. We performed a population pharmacokinetic analysis with NONMEM and determined that the steady-state pharmacokinetics of saquinavir in 136 HIV type 1-infected adults was modulated by a decrease in saquinavir CL following coadministration of the cytochrome P450 3A inhibitors ritonavir and atazanavir. In contrast, age, sex, weight, pregnancy, and the pharmaceutical formulation exerted only minor, nonsignificant effects.The human immunodeficiency virus type 1 (HIV-1) protease inhibitor saquinavir (1,000 mg twice daily) is a well-established component of antiretroviral therapy (3, 7). Antiretrovirally effective plasma concentrations above the in vitro 90% inhibitory concentration of 5 to 80 nM (12) are clinically obtained by decreasing saquinavir's metabolic clearance (CL) following coadministration of 100 mg of the cytochrome P450 3A (CYP3A) blocking agent ritonavir (4,7,8). However, too-low or too-high concentrations jeopardize the therapy success or produce side effects, respectively (10, 13). Therefore, factors affecting plasma saquinavir concentrations are of clinical relevance.(A subset of these data was published previously [10].) Population pharmacokinetics is receiving increasing acceptance for exploration and definition of relevant sources of variation in drug exposure and responses (1). We used it to assess the relative contributions of ritonavir and atazanavir coadministration (2,5,14), of demographic factors, and of the pharmaceutical formulation (9) to the modulation of plasma saquinavir concentrations. HIV-1-infected patients (n ϭ 136) received 1,000 mg saquinavir twice daily, either as soft gel capsules (Fortovase; n ϭ 52) or hard gel capsules (Invirase; n ϭ 84) containing 200 mg saquinavir mesylate (Hoffmann-La Roche, Basel, Switzerland) together with 100 mg ritonavir (Norvir; Abbot GmbH, Wiesbaden, Germany). Atazanavir (300 mg once daily; Reyataz; Bristol Myers Squibb GmbH, Baar, Switzerland) was administered to 49 patients (43 men, 6 nonpregnant women) in whom reverse transcriptase inhibitors had had toxic effects or were ineffective due to viral resistance.Nucleosidic reverse transcriptase inhibitors were administered to the other 87 patients.The study cohort comprised 104 HIV-1-infected men, aged 20 to 71 years (median, 41.5 years) and weighing 51 to 116 kg (median, 74 kg), and 32 HIV-1-infected women, aged 19 to 64 years (median, 32.5 years) and weighing 42 to 100 kg (median, 68.5 kg), of which 13 were pregnant (mean ϭ 32 weeks ϩ 4 days, range ϭ 24 weeks ϩ 3 days to 36 weeks ϩ 5 days). Subjects with any CD4 cell count or viral load at baseline of therapy were included. Patients with functional impairment of the liver (Child-Pugh classification B or C [11]) and patients taking CYP3A4-modulating cotherapies other than the presented antiretrovirals were excluded.A 12-h plasma drug concen...