Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy.

ObjectivesTo assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy.Patients and methodsLopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (>1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy.ResultsThe median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and volume of distribution (V/F). Population estimates of lopinavir CL/F and V/F were 6.21 L/h/70 kg and 52.6 L/70 kg, respectively. Based on simulations, the highest risk of subtherapeutic trough concentrations was for women weighing >100 kg using the standard dose (∼ 7%), while the risk was <2% with the 600/150 mg dose for women weighing 40-130 kg. After a missed dose, 61% of women have lopinavir concentrations below target prior to the next dose with the standard dose compared with 42% with the increased dose.ConclusionsStandard dosing provides adequate lopinavir trough concentrations for the majority of pregnant women but increased doses may be preferable for women weighing >100 kg and with a history of lopinavir/ritonavir use and/or adherence issues

Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy

Objective: To evaluate the pharmacokinetics and HIV viral load response following initiation during the third trimester of pregnancy of zidovudine plus standard-dose lopinavir boosted with ritonavir (LPV/r), twice daily, until delivery for the prevention of mother-to-child transmission of HIV. Design: Prospective study nested within a multicenter, three-arm, randomized, phase III prevention of mother-to-child transmission of HIV trial in Thailand (PHPT-5, ClinicalTrials.gov Identifier: NCT00409591). Methods: Women randomized to receive 300 mg zidovudine and 400/100 mg LPV/r twice daily from 28 weeks' gestation, or as soon as possible thereafter, until delivery had intensive steady-state 12-h blood sampling performed. LPV/r pharmacokinetic parameters were calculated using noncompartmental analysis. Rules were defined a priori for a LPV/r dose escalation based on the proportion of women with an LPV area under the concentration–time curve (AUC) below 52 μg h/ml (10th percentile for LPV AUC in nonpregnant adults). HIV-1 RNA response was assessed during the third trimester. Results: Thirty-eight women were evaluable; at entry, median (range) gestational age was 29 (28–36) weeks, weight 59.5 (45.0–91.6) kg, CD4 cells count 442 (260–1327) cells/μl and HIV-1 RNA viral load 7818 (<40–402 015) copies/ml. Geometric mean (90% confidence interval) LPV AUC, Cmax and Cmin were 64.6 (59.7–69.8) μg h/ml, 8.1 (7.5–8.7) μg/ml and 2.7 (2.4–3.0) μg/ml, respectively. Thirty-one of 38 (81%) women had an LPV AUC above the AUC target. All women had a HIV-1 viral load less than 400 copies/ml at the time of delivery. Conclusion: A short course of zidovudine plus standard-dose LPV/r initiated during the third trimester of pregnancy achieved adequate LPV exposure and virologic response

Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy.

ObjectivesTo assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy.Patients and methodsLopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (&gt;1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy.ResultsThe median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and volume of distribution (V/F). Population estimates of lopinavir CL/F and V/F were 6.21 L/h/70 kg and 52.6 L/70 kg, respectively. Based on simulations, the highest risk of subtherapeutic trough concentrations was for women weighing &gt;100 kg using the standard dose (∼ 7%), while the risk was &lt;2% with the 600/150 mg dose for women weighing 40-130 kg. After a missed dose, 61% of women have lopinavir concentrations below target prior to the next dose with the standard dose compared with 42% with the increased dose.ConclusionsStandard dosing provides adequate lopinavir trough concentrations for the majority of pregnant women but increased doses may be preferable for women weighing &gt;100 kg and with a history of lopinavir/ritonavir use and/or adherence issues

Transmission probabilities according to zidovudine duration, viral load at baseline/delivery, and nevirapine intake.

<p>A. Probability of <i>in-utero</i> HIV transmission as a function of zidovudine duration; B. Probability of <i>in-utero</i> HIV transmission as a function of viral load at baseline. The lines denote the median, 5^th and 95^thpercentiles of the model predictions. The open circles stand for the observed mean proportion of transmission, the solid vertical segments denote the corresponding 95% confidence intervals (numbers at top of each segment stand for the number of women in each time interval or VL interval). C. Probability of <i>intra-partum</i> HIV mother-to-child transmission as a function of viral load at delivery without single dose nevirapine; D. Probability of <i>intra-partum</i> HIV mother-to-child transmission as a function of viral load at delivery with single dose nevirapine.</p

Diagnostic plots for viral load time-course model.

<p>Top: 2a and 2b: Observed versus model predicted viral load values (expressed as log₁₀ copies) of the population and individual predictions respectively. Solid black circles, measure values; grey symbols, simulation of below the limit of quantification data. Line, identity line. Bottom: Visual predictive check plots. (2c) Women receiving only zidovudine (ZDV); (2d) women receiving zidovudine plus lopinavir/ritonavir (ZDV+LPV/r).The lines denote the median, 5^th and 95^th percentiles for the observed data. The grey areas stand for the 95% confidence intervals of the median, 5^th and 95^th model prediction percentiles.</p

The univariate and multivariable analyses of the HIV intra-partum transmission model using data from 3,707 HIV-1-infected mothers enrolled in the PHPT-1, PHPT-2, and PHPT-5 studies.

<p>^aRSE%, relative standard error (standard error of estimate / estimate*100)</p><p>^b Bayesian Information Criterion</p><p>^c Random effect of individuals: <i>η</i>~<i>N</i>(0,0.73²)</p><p>The univariate and multivariable analyses of the HIV intra-partum transmission model using data from 3,707 HIV-1-infected mothers enrolled in the PHPT-1, PHPT-2, and PHPT-5 studies.</p

The univariate and multivariable analyses of the HIV <i>in-utero</i> model using data from 3,707 HIV-1-infected mothers enrolled in the PHPT-1, PHPT-2, and PHPT-5 studies.

<p>^a RSE%, relative standard error (standard error of estimate / estimate*100)</p><p>^b Bayesian Information Criterion</p><p>^c Random effect of individuals: <i>η</i>~<i>N</i>(0,0.527²)</p><p>The univariate and multivariable analyses of the HIV <i>in-utero</i> model using data from 3,707 HIV-1-infected mothers enrolled in the PHPT-1, PHPT-2, and PHPT-5 studies.</p