Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir

Abstract

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

Keywords: NONMEM; abacavir; children; lopinavir; population pharmacokinetics; rifampin.

FIG 1

(Top) Visual predictive check of abacavir concentration versus time after dose, stratified by PK visit. PK visit 1 is the intensive phase of antituberculosis treatment with LPV/r-4:4, PK visit 2 is the continuation phase of antituberculosis treatment with LPV/r-4:4, and PK visit 3 represents 1 month after antituberculosis treatment completion on LPV/r-4:1. The solid and dashed lines represent the 50th, 5th, and 95th percentiles of the observed data, while the shaded areas represent the model-predicted 95% confidence intervals for the same percentiles. The dots are the observed concentrations. The yellow ticks on the x axis are bin boundaries. (Bottom) Proportion of LLOQ values versus time after dose. The solid blue line represents the observed proportion, while the blue shaded area is the 90% confidence interval for the same proportion, as predicted by the model.

FIG 2

Maturation function of abacavir clearance versus postmenstrual age (bottom x axis) or postnatal age (top x axis; assuming an average gestation of 9 months), after adjusting for weight. The solid vertical blue line represents birth, while the dashed vertical lines represent 1 year and 2 years of postnatal age. The red ticks on the lower x axis represent the postmenstrual age values available in our data.

FIG 3

Simulated steady-state abacavir AUC_0–12 versus body weight. (Left) Exposures during cotreatment with superboosted LPV/r-4:4 and rifampin; (right) exposures during cotreatment with unboosted LPV/r-4:1. The box indicates the interquartile range, while the whiskers denote the 2.5th and the 97.5th percentiles. The green box plots show the exposures of children weighing from 3 to 24.9 kg receiving the current pediatric dosing, as shown in Table 4, while the red box plots show the predicted exposure in adults weighing 25 to 39.9 kg and 40 to 59.9 kg, with children receiving a dose of 300 mg twice daily and adults receiving a dose of 600 mg once daily. The adult AUC_0–24 was divided by 2 to obtain a value comparable to the AUC_0–12 for comparison to the children’s exposures. The red horizontal dashed line represents the recommended median adult exposure (6.02 mg·h/liter). The weights of the children in this study population were mostly in the range of 4 to 16 kg; all the results outside this weight range (boxes with faint color) were extrapolated using maturation and allometric scaling. To improve the readability of the chart, the y axis was cut; the 97.5th percentile predicted AUC for children in the 3-kg weight band reached 67 mg·h/liter.

FIG 4

Summary of model-predicted abacavir AUC_0–12 versus weight bands in each pharmacokinetic visit. The box indicates the interquartile range, while the whiskers denote the 2.5th and the 97.5th percentiles. Each dot represents an individual AUC. PK visit 1 is the intensive phase of antituberculosis treatment with LPV/r-4:4, PK visit 2 is the continuation phase of antituberculosis treatment with LPV/r-4:4, and PK visit 3 represents 1 month after the completion of antituberculosis treatment with LPV/r-4:1. The red horizontal solid line represents the reference median AUC, while the broken lines represent adult AUC values from the literature: Yuen et al. (7) (dashed orange line), Moyle et al. (17) (long-dash black line), McDowell et al. (6) (dot-dash green line), and Weller et al. (43) (dotted blue line).