Virological, intracellular and plasma pharmacological parameters predicting response to lopinavir/ritonavir (KALEPHAR Study)

Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC 0 -12 ) and maximum concentration were ϳ15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.A ntiretroviral therapies (ARTs), with the exception of zidovudine, are unlicensed for use in pregnancy. However, they are widely used, in accordance with national and international guidelines, both for maternal treatment and for the prevention of HIV mother-to-child transmission (MTCT). Multiple physiological changes which can impact the pharmacokinetics (PKs) of these agents occur during pregnancy; therefore, studies in pregnancy are required to ensure appropriate dosing and avoid unnecessary toxicity or treatment failure. Protease inhibitors (PIs) are widely used during pregnancy for both treatment and prevention of MTCT due to their efficacy, lack of CD4 count-dependent toxicity, and short half-lives (t 1/2 s). However, plasma concentrations of certain protease inhibitors have repeatedly been shown to be significantly reduced during the third trimester, with some concerns over efficacy (37).Lopinavir (LPV)-ritonavir (RTV), or LPV/r, is used during pregnancy,...

Section: Discussionmentioning

confidence: 99%

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Else

Douglas

Dickinson

et al. 2012

“…As LPV plasma concentrations and the genotype inhibitory quotient have been related to virological efficacy in experienced patients on LPVr-based regimens (16)(17)(18)(19), in this study, we tested whether low plasma LPV trough concentrations contribute to VF throughout the mtLPVr treatment period. The confirmation of this hypothesis would demonstrate that LPV therapeutic drug monitoring could be useful in improving the efficacy of LPV when prescribed as a monotherapy.…”

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confidence: 99%

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

López‐Cortés

Ruiz-Valderas

Sánchez-Rivas

et al. 2013

There is significant intra-and intersubject variability in lopinavir (LPV) plasma concentrations after standard dosing; thus, this prospective study was conducted to determine whether low plasma LPV concentrations could be associated with virological outcome throughout lopinavir-ritonavir maintenance monotherapy (mtLPVr) in the clinical practice setting. If this hypothesis would be confirmed, LPV drug monitoring could improve the efficacy of mtLPVr regimens. Patients with previous virological failure (VF) on protease inhibitor-based regimens were also included if the genotypic resistance tests showed no major resistance mutation associated with reduced susceptibility to lopinavir-ritonavir. VF was defined as 2 consecutive determinations of HIV RNA levels of >200 copies/ml. Efficacy was analyzed by per-protocol analysis. Plasma LPV trough concentrations were measured by high-performance liquid chromatography using a UV detector. A total of 127 patients were included (22% with previous failure on protease inhibitors). After 96 weeks, the efficacy rate was 82.3% (95% confidence interval [CI 95 There is significant controversy regarding ritonavir-boosted protease inhibitor (PI) monotherapy as a maintenance therapeutic strategy (1-5). Notwithstanding, a considerable proportion of patients maintained an undetectable viremia on lopinavirritonavir maintenance monotherapy (mtLPVr) and could benefit from a simpler regimen without nucleoside analogues or other antiretroviral drugs. Moreover, lack of adherence has been indicated as the main reason for virological failure (VF) in different studies (6-13).Moreover, there is significant intra-and intersubject variability in LPV plasma concentrations after standard dosing, determined largely by variability in drug absorption, cytochrome P450 metabolism, plasma protein binding, and drug transporter activity, which may affect the disposition of the drug (14, 15). As LPV plasma concentrations and the genotype inhibitory quotient have been related to virological efficacy in experienced patients on LPVr-based regimens (16)(17)(18)(19), in this study, we tested whether low plasma LPV trough concentrations contribute to VF throughout the mtLPVr treatment period. The confirmation of this hypothesis would demonstrate that LPV therapeutic drug monitoring could be useful in improving the efficacy of LPV when prescribed as a monotherapy. MATERIALS AND METHODSStudy population and design. From April 2009 to April 2010, adult HIV-1-infected patients who started a regimen of mtLPVr at our outpatient clinic were consecutively included in this observational, prospective, open-label study. The LPVr dosing regimen (400 mg of LPV and 100 mg of ritonavir twice daily or 800 mg-200 mg once daily) was selected by the patients' physicians. All subjects had plasma HIV RNA levels of Ͻ50 copies/ml for at least 6 months. Patients with VF while on a PI-containing regimen were also included in the study when genotypic resistance tests showed no major or Յ3 minor resistance mutations associated with reduced...

“…Different LPV C trough targets have been proposed for PI-naïve patients (1 mg/liter) (20) and for PIexperienced patients (3 to 5.7 mg/liter) (5,6,8,27). A more comprehensive target, the phenotypic inhibitory quotient (PIQ), incorporates viral drug susceptibility, which is measured as the concentration of drug required to achieve 50% in vitro inhibition of replication of the virus (IC 50 ) relative to the replication of human immunodeficiency virus (HIV) in drugfree medium.…”

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confidence: 99%

Population Pharmacokinetics of Lopinavir Predict Suboptimal Therapeutic Concentrations in Treatment-Experienced Human Immunodeficiency Virus-Infected Children

Rakhmanina¹,

Anker

Baghdassarian³

et al. 2009

In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R 2 of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.Lopinavir/ritonavir (LPV/RTV) (Kaletra) is the first and only coformulated RTV-boosted protease inhibitor (PI) approved for use in children. The recommended doses for children who weigh more than 15 kg are 10 mg/kg of body weight or 230 mg/m 2 (body surface area) twice daily, with a maximum of 400 mg per dose unless it is combined with drugs affecting cytochrome (CYP) P450 metabolism, which require LPV dose adjustment (4, 28). Introduced as a salvage agent (22), LPV/RTV has become one of the preferred PI choices for first-line regimens in children Ͼ6 months of age in the countries with access to the drug.Despite evidence for good antiviral efficacy among children in a clinical trial setting (16,17,23), the standard dose may not be adequate for every child. Noncompartmental analysis has shown that the average LPV plasma 12-hour-postdose concentration (C trough ) in children given the currently recommended pediatric dose of LPV is 67% lower than in adults (24). Recently, Jullien et al. published a population pharmacokinetics (PK) model of LPV in children aged 0 to 18 years (15). The model was based on a retrospective analysis of LPV plasma measurements in 157 children, with a median of 3 samples (range, 1 to 14) per patient, obtained for monitoring purposes after self-reported LPV intake. In t...