Pharmacokinetic and Pharmacodynamic Comparison of Once‐Daily Efavirenz (400 mg vs. 600 mg) in Treatment‐Naïve HIV‐Infected Patients: Results of the ENCORE1 Study

Dickinson, Laura; Amin, Janaki; Else, Laura; Boffito, Marta; Egan, Deirdre; Owen, Andrew; Khoo, SH; Back, David; Orrell, Catherine; Clarke, Amanda; Losso, Marcelo; Phanuphak, Praphan; Carey, Dianne; Cooper, D.; Emery, Sean; Puls, Rebekah

doi:10.1002/cpt.156

Cited by 70 publications

(90 citation statements)

References 35 publications

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“…For DOR, at a daily dose of 100 mg (the dose employed in the phase 3 clinical trials), the plasma trough concentration at 24 h is 830 nM. The trough concentrations of EFV and RPV are 5,600 nM and 260 nM at 24 h at clinical doses of 600 mg and 25 mg, respectively (18,19). These values and the respective IC 50 s determined in the presence of 100% serum were used to calculate IQs for each of these drugs versus the panel of NNRTI mutants, as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Feng

Sachs

et al. 2016

Antimicrob Agents Chemother

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Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC 50 s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC 50 for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting.T he introduction of highly active antiretroviral therapy (HAART) in 1996 has significantly reduced the morbidity and mortality associated with HIV-1 infection (1, 2). However, the clinical and immunologic benefits of antiretroviral therapy can be compromised by the emergence of drug-resistant viruses due to suboptimal treatment or adherence.Drug-resistant mutants can be transmitted to an uninfected individual. Transmitted drug-resistant (TDR) mutants limit the choice of first-line combination antiretroviral therapy, decrease the efficacy of subsequent antiretroviral regimens, and increase the risk of treatment failure (3-5). TDR mutants have been documented among treatment-naive patients, with prevalences ranging from 3% to 24%, depending on the cohort and geographic characteristics (6). Importantly, transmitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants are of particular concern, as they have the ability to persist for years after initial infection, suggesting the low impact of NNRTI-resistant mutations on viral fitness (7-9). The persistence of NNRTI-associated mutants after the discontinuation of an NNRTI-containing regimen may contribute to the prevalence of NNRTI-associated TDR mutants.Three mutants, K103N, Y181C, and G190A, account for Ͼ90% of the NNRTI-associated TDR mutants in the United States (10). K103N, Y181C, and K103N/Y181...

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Section: Resultsmentioning

confidence: 99%

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Feng

Sachs

et al. 2016

Antimicrob Agents Chemother

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“…The recent results of ENCORE1, 24,25 showing that the standard 600 mg efavirenz dose can be reduced to 400 mg daily without loss of efficacy in nonpregnant adults, have prompted discussions on the validity of the widely accepted efficacy thresholds of >1 mg/L, for a mid-dose interval or trough concentration, 25 and suggest that the target range used for children should also be reevaluated. Our analysis therefore aimed to characterize associations between systemic exposure to efavirenz and risk of virological nonsuppression and CNS AEs over the longer term, to identify factors affecting virological nonsuppression independently of systemic exposure, and to validate the lower boundary of the therapeutic range for efavirenz in African children.…”

Section: Introductionmentioning

confidence: 99%

Plasma Efavirenz Exposure, Sex, and Age Predict Virological Response in HIV-Infected African Children

Bienczak

Denti

Cook

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…versus 600 mg q.d. conducted as part of the ENCORE (Exercise and Nutritional Interventions for Cardiovascular Health) I study was recently published (6). Three years before this clinical analysis, we published a prediction about the 400-mg exposure of this drug that was made by using PBPK modeling (7).…”

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confidence: 99%

Validation of Computational Approaches for Antiretroviral Dose Optimization

Siccardi

Dickinson

Owen

2016

Antimicrob Agents Chemother

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Strategies for reducing antiretroviral doses and drug costs can support global access, and numerous options are being investigated. Efavirenz pharmacokinetic simulation data generated with a bottom-up physiologically based model were successfully compared with data obtained from the ENCORE (Exercise and Nutritional Interventions for Cardiovascular Health) I clinical trial (efavirenz at 400 mg once per day versus 600 mg once per day). These findings represent a pivotal paradigm for the prediction of pharmacokinetics resulting from dose reductions. Validated computational models constitute a valuable resource for optimizing therapeutic options and predicting complex clinical scenarios. Global access to treatment would result in a more effective strategy against the HIV pandemic, but there are several challenges in terms of drug production and distribution. Antiretroviral dosing strategies have been selected to inhibit viral replication, but there is growing recognition that some antiretroviral drugs may be administered at doses above those required for efficacy. This may place a higher demand than necessary on medication budgets and manufacturing costs in resource-limited settings, where the need for these medications is greatest.Alternative strategies for lowering doses and drug costs could effectively support global access, and several reduction strategies are being investigated (1). A rational identification of optimal dose reductions is challenging and is commonly based on results from large clinical studies.Drug distribution can be quantitatively investigated through computational approaches using data from clinical studies to provide a top-down description and its variability in populations (i.e., population pharmacokinetic [popPK] modeling) or integrating drug-specific in vitro data in models to predict bottom-up pharmacokinetics (PK) in populations of virtual patients (i.e., physiologically based pharmacokinetic [PBPK] modeling). PBPK modeling is based on the mathematical representation of absorption, distribution, and elimination processes that define pharmacokinetics (2). Drug-specific factors (lipophilicity, apparent permeability, in vitro clearance, induction, and inhibition potential) and patient-specific factors (demographics, enzyme expression, organ volume, and blood flows) are integrated to provide a realistic description of pharmacokinetics (3)(4)(5). A virtual population of patients can be simulated by considering anatomical and physiological characteristics and their covariances.A pharmacokinetic assessment after administration of efavirenz (EFV) at 400 mg once daily (q.d.) versus 600 mg q.d. conducted as part of the ENCORE (Exercise and Nutritional Interventions for Cardiovascular Health) I study was recently published (6). Three years before this clinical analysis, we published a prediction about the 400-mg exposure of this drug that was made by using PBPK modeling (7).The purpose of this work is to exemplify the utility of PBPK modeling in exploring the pharmacokinetic consequences of dose r...

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Pharmacokinetic and Pharmacodynamic Comparison of Once‐Daily Efavirenz (400 mg vs. 600 mg) in Treatment‐Naïve HIV‐Infected Patients: Results of the ENCORE1 Study

Cited by 70 publications

References 35 publications

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Plasma Efavirenz Exposure, Sex, and Age Predict Virological Response in HIV-Infected African Children

Validation of Computational Approaches for Antiretroviral Dose Optimization

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