Population pharmacokinetics of lopinavir in combination with ritonavir in HIV‐1‐infected patients

Crommentuyn, Kristel M. L.; Kappelhoff, Bregt S; Mulder, J.; Mairuhu, Albert T.A.; Gorp, Eric C. M. Van; Meenhorst, Pieter L.; Huitema, Alwin D. R.; Beijnen, Jos H.

doi:10.1111/j.1365-2125.2005.02455.x

Cited by 69 publications

(66 citation statements)

References 34 publications

(30 reference statements)

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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). The model was qualified using both bootstrapping and visual predictive checks.…”

Section: Discussionsupporting

confidence: 71%

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: 71%

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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“…The variabilities, BSV and residual, remained at high levels, as previously observed in other childhood studies [1,2,4]. In adults, the residual variability, approximated to 0.21 [from the additive 1.15 mg l -1 and proportional 0.075 components reported, 0.21 = square root ((1.15/ 6) 2 + 0.075 2 ] was lower and BSVs were estimated via a full variance-covariance matrix, explaining in part a lower BSV(CL) value, 0.17 [3]. The high correlation between CL/F and V/F BSVs (r = 0.86) also supports the importance of bioavailability to explain these high variabilities.…”

Section: Discussionmentioning

confidence: 92%

“…Because of the availabilty of the oral formulation, lopinavir is administered to neonates having a high risk of perinatal or postnatal motherto-child transmission of HIV. In infants and children, studies have shown a fast elimination half-life of LPV/r as compared with adults [1][2][3][4]. LPV is a substrate of CYP3A4, immature in neonates compared with infants and children,and could be associated with a specific pharmacokinetic profile in the first weeks after birth [5].…”

Section: Introductionmentioning

confidence: 99%

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

Urien

Firtion

Anderson

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Lopinavir/ritonavir pharmacokinetics have been fully investigated in adults and children. WHAT THIS STUDY ADDS• Lopinavir/ritonavir population pharmacokinetics in 96 neonates and infants from birth to less than 2 years (1.16 to 10.4 kg) showed that CL/F and V/F were dependent on body weight on an allometric basis and post-menstrual age. AIMSBecause of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg. METHODSLopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach. RESULTSA one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h -1 70 kg -1 and 91.7 l 70 kg -1. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks. CONCLUSIONSSize and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h -1 , 80 mg 12 h -1 and 120 mg 12 h -1 in the 1-2 kg, 2-6 kg and 6-10 kg group, respectively.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2011 956 / Br J Clin Pharmacol / 71:6 / 956-960

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“…Other studies have suggested that the currently recommended dose of LPV/RTV might result in suboptimal exposure in HIV-infected children (4,10,24). Based on our PK model and the LPV pharmacodynamic models by Hsu et al and Podzamczer et al (13,21), we have shown that the majority of children are unlikely to achieve therapeutic plasma LPV concentrations against virus that is moderately resistant to LPV, at degrees far below the clinical cutoffs suggested by current phenotypic resistance testing.…”

Section: Discussionmentioning

confidence: 93%

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

Rakhmanina¹,

Anker

Baghdassarian³

et al. 2009

Antimicrob Agents Chemother

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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...

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Population pharmacokinetics of lopinavir in combination with ritonavir in HIV‐1‐infected patients

Cited by 69 publications

References 34 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

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

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

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