Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

Wang, Kun; D’Argenio, David Z.; Acosta, Edward P.; Sheth, Anandi N.; Delille, Cecile; Lennox, Jeffrey L.; Kerstner-Wood, Corenna; Ofotokun, Ighovwerha

doi:10.1007/s40262-013-0122-1

Cited by 12 publications

(16 citation statements)

References 42 publications

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“…The final model estimates for LPV clearance and volume of distribution in nonpregnant subjects were similar to those of previously published pharmacokinetic studies (27,28). RTV concentrations increased LPV concentrations, with an IC 50 of 0.239 g/ml in this model, which reflects the potency of the RTV inhibitory effect on LPV clearance and is consistent with prior estimates (29,30).…”

Section: Discussionsupporting

confidence: 84%

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No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Salem

Jones

Santini-Oliveira

et al. 2016

Antimicrob Agents Chemother

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Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC 0 -12 ) and concentration prior to dosing (C predose ) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC 0 -12 or C predose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.T he use of combination antiretroviral therapy (cART) is recommended in all pregnant women with HIV infection for prevention of perinatal transmission as well as for maternal health. Such use has resulted in a significant reduction of perinatal transmission from 25% to 0 -3.6% (1, 2). Treatment guidelines include the use of protease inhibitors in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) (3-7).Lopinavir (LPV) is a peptidomimetic HIV type 1 (HIV-1) protease inhibitor. When LPV is coadministered with low-dose ritonavir (RTV), which acts as a pharmacokinetic enhancer by blocking the cytochrome P450 3A (CYP3A)-mediated metabolism of LPV, serum levels of LPV are significantly increased, and half-life is prolonged. The high LPV exposures achieved with coformulated lopinavir-ritonavir (LPV/r) have the advantage of providing a pharmacologic barrier to the emergence of HIV-1 viral resistance in patients with wild-type virus, as well as enhanced activity against some forms of drug-resistant HIV-1 (8).Because of the potency of ...

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Section: Discussionsupporting

confidence: 84%

“…First, RTV inhibition of LPV clearance was modeled using a competitive inhibition model according to the following equation (27)…”

Section: Methodsmentioning

confidence: 99%

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Salem

Jones

Santini-Oliveira

et al. 2016

Antimicrob Agents Chemother

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“…This is probably because the clinical study was not designed to detect the interaction; therefore, the data are not ideal for quantifying this, given the small sample size and time‐varying pharmacokinetics inherent in the study design. Nevertheless, our analysis reports an interaction coefficient of 0.0028, or 0.00041 in terms of total RTV concentration, which is consistent with the interaction value of 0.00064 reported by Wang et al, using the same interaction function form.…”

Section: Discussionsupporting

confidence: 92%

Model‐Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV‐Infected Pregnant Women Supports Standard Dosing in the Third Trimester

Chen

Malone

Prince

et al. 2016

CPT Pharmacom & Syst Pharma

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Physiological changes during pregnancy can affect drug pharmacokinetics. Here we present a population pharmacokinetic model to describe the longitudinal change of unbound lopinavir/ritonavir (LPV/RTV) PK parameters with gestational age, and to predict unbound LPV concentrations under different dosing regimens. The changes in apparent intrinsic clearances of LPV and RTV during pregnancy are described using an exponential function of gestational age. The unbound fractions of LPV/RTV are not significantly different between pregnancy and postpartum. Simulation reveals that despite increases in LPV intrinsic clearance, effective LPV inhibitory quotient (IQ) values are predicted with the standard dosing (400/100 mg b.i.d.) in >90% of simulations, with ≤4‐fold increase in viral IC50. As viral susceptibility decreases, higher doses increase the likelihood of efficacy. With ≥40‐fold increases in IC50, IQs suggest alternate regimens be considered. This approach refines previous LPV PK reports, and supports that standard dosing is effective with susceptible virus.

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“…In this study, the typical apparent CL of LPV was 5.9 L/h for 70‐kg patients, which is comparable to that found in Caucasians (4.73‐5.73 L/h) . No obvious differences in the PK of LPV were found between Chinese and Caucasians.…”

Section: Discussionsupporting

confidence: 78%

“…To the best of our knowledge, this is the first reported PPK model of LPV in Chinese adult patients infected with HIV. The PK of LPV was best described using a one‐compartment model with first‐order absorption and lag time, similar to that in previous studies of a non‐Asian population. WT was identified as the only covariate influencing CL.…”

Section: Discussionmentioning

confidence: 74%

Population pharmacokinetics and dosing regimen optimisation of lopinavir in Chinese adults infected with HIV

Niu

Sun

Liu

et al. 2018

Basic Clin Pharma Tox

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Lopinavir (LPV) is a protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infections. Current studies on LPV are mainly focused onCaucasians, and none have investigated the population pharmacokinetics (PPK) of LPV in Chinese population. The present study aimed to develop a PPK model for oral LPV in Chinese adults who are HIV-infected. A total of 460 LPV concentrations from 174 Chinese patients who received LPV/ritonavir (LPV/r) 400/ 100 mg orally every 12 hours (q12h) were analysed using the non-linear mixedeffects modelling approach. Simulations of the LPV concentration profile were performed with different dosing regimens. A one-compartment model with firstorder absorption and elimination process described the data. The estimated apparent clearance (CL/F) and volume of distribution (V/F) (% relative standard error [RSE]) for oral LPV were 5.9 L/h (3%) and 117 L (8%), respectively. Bodyweight was identified as a covariate on CL/F. In patients who weighed between 45 and 115 kg and received the standard 400/100 mg q12h regimen, the probability of achieving target trough concentration (C trough ) of 1 mg/L was >98% for PInaïve patients and the probability of achieving target C trough of 4 mg/L was <80% for PI-pretreated patients. This is the first population pharmacokinetic study to characterise the PK of LPV in Chinese patients with HIV infection. There were no obvious ethnic differences in the PK of LPV between the Chinese population and Caucasian population. The simulations demonstrated that the standard dosing regimen of 400/100 mg q12h (LPV/r tablets) appears to be sufficient for PI-naïve patients but suboptimal for PI-pretreated patients. Therefore, the regimen of 800/ 200 mg q12h was recommended for PI-pretreated patients. Further investigation of dosage recommendation could be helpful in optimising LPV therapy for HIV infections. K E Y W O R D SChinese patients, HIV, lopinavir, population pharmacokinetics, ritonavir, simulation Niu and Sun contributed equally to this work.

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Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naïve Patients

Cited by 12 publications

References 42 publications

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Model‐Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV‐Infected Pregnant Women Supports Standard Dosing in the Third Trimester

Population pharmacokinetics and dosing regimen optimisation of lopinavir in Chinese adults infected with HIV

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