The Effect of Malnutrition on the Pharmacokinetics and Virologic Outcomes of Lopinavir, Efavirenz and Nevirapine in Food Insecure HIV-infected Children in Tororo, Uganda

Bartelink, Imke H.; Savic, Rada; Dorsey, Grant; Ruel, Theodore; Gingrich, David; Scherpbier, Henriëtte J.; Capparelli, Edmund V.; Jullien, Vincent; Young, Sera L.; Achan, Jane; Plenty, Albert; Charlebois, Edwin D.; Kamya, Moses R.; Havlir, Diane V.; Aweeka, Francesca

doi:10.1097/inf.0000000000000603

Cited by 30 publications

(41 citation statements)

References 58 publications

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“…This technique provides a semimechanistic platform to interpret pharmacokinetic data able to adjust for the concomitant effect of multiple factors. The population pharmacokinetics of lopinavir and ritonavir in children (38)(39)(40)(41)(42) and in children cotreated with first-line antituberculosis drugs (18,20) have been described in previous published reports. We aimed to characterize the effects of antituberculosis drugs routinely used for the treatment of MDR-TB on the pharmacokinetics of lopinavir and ritonavir in HIV-infected children.…”

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confidence: 99%

Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis

Laan

Garcia-Prats

Schaaf

et al. 2018

Antimicrob Agents Chemother

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Lopinavir-ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin and 16 without TB) who were established on a lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size.

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confidence: 99%

Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis

Laan

Garcia-Prats

Schaaf

et al. 2018

Antimicrob Agents Chemother

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“…Our findings demonstrate the utility of PBPK modeling for dose optimization, and a comparison between bottom-up and top-down approaches can build the basis for a future wider application of this modeling approach (11)(12)(13). The pharmacology of antiretrovirals and other anti-infective drugs is based on the coadministration of complex regimens, and these drugs are often administered to patients with specific characteristics that result in challenging clinical scenarios (14,15). Computational predictive models, such as the PBPK model, can represent a pivotal resource from which to answer questions that cannot otherwise be examined in preclinical or clinical development, can support the rational design of therapeutic options and can identify strategies for maximizing the efficiency and safety of therapies in various populations of patients.…”

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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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“…Other studies found lower nevirapine concentrations in stunted children compared with nonstunted children . Efavirenz and LPV exposures were reduced in Ugandan children, 48% of whom were malnourished, compared to historical data from children in resource‐rich countries . From a previous report of this study cohort, LPV PK were influenced by patients' fat free mass, but not by timing of ART initiation pending nutritional rehabilitation or tuberculosis (TB) comedication.…”

Section: Introductionmentioning

confidence: 65%

“…12,21 Efavirenz and LPV exposures were reduced in Ugandan children, 48% of whom were malnourished, compared to historical data from children in resource-rich countries. 22 From a previous report of this study cohort, LPV PK were influenced by patients' fat free mass, but not by timing of ART initiation pending nutritional rehabilitation or tuberculosis (TB) comedication. However, the PK of LPV was found to be highly variable with reduced bioavailability, resulting in a greater apparent clearance (CL/F) in this cohort.…”

Section: Introductionmentioning

confidence: 82%

Population pharmacokinetics of abacavir and lamivudine in severely malnourished human immunodeficiency virus‐infected children in relation to treatment outcomes

Archary

Mcllleron

Bobat

et al. 2019

Brit J Clinical Pharma

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Aims Describe the pharmacokinetics (PK) of the antiretroviral drugs abacavir and lamivudine in malnourished paediatric patients and relate to viral load outcomes after 12 and 48 weeks of treatment. Methods Severely malnourished human immunodeficiency virus‐infected children were randomized to early (within 14 days) or delayed (after nutritional recovery) initiation of antiretroviral treatment (ART) using World Health Organization weight‐band dosages. Abacavir and lamivudine concentrations were measured as a secondary objective on day 1 and day 14 and patients were followed‐up to week 48. Population PK of abacavir and lamivudine were described using NONMEM. Results In total, 623 abacavir and 627 lamivudine concentrations were collected from 75 paediatric patients aged 0.1–10.8 (median 1.4) years. Abacavir PK was described by a 2‐compartment model, patients randomized to early ART showed increased bioavailability of 31%. Apparent clearance (CL/F, L/h/7 kg) of abacavir increased from day 1 to day 14 from 3.33 (95% confidence interval 2.71–4.12) to 5.86 (95% confidence interval 4.78–7.3). A 1‐compartment model described lamivudine PK, variability on CL/F was explained by maturation with age, with age at half‐matured CL/F being 4 months. For both drugs allometrically scaled total body weight was related to CL/F and apparent volume of distribution. PK exposure did not correlate with virological outcomes or death at 12 or 48 weeks. Conclusion Increases in Abacavir's CL/F between day 1 to day 14, bioavailability and PK variability with early start of ART was found in this cohort of severely malnourished children; however, these changes did not influence virological outcomes. The study supports the use of weight‐band dosage tables.

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The Effect of Malnutrition on the Pharmacokinetics and Virologic Outcomes of Lopinavir, Efavirenz and Nevirapine in Food Insecure HIV-infected Children in Tororo, Uganda

Cited by 30 publications

References 58 publications

Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis

Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis

Validation of Computational Approaches for Antiretroviral Dose Optimization

Population pharmacokinetics of abacavir and lamivudine in severely malnourished human immunodeficiency virus‐infected children in relation to treatment outcomes

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