Lopinavir/Ritonavir Super-boosting Overcomes Interactions In Children Treated With Rifampicin: A Model-Based Approach For Non-Inferiority Trials
Paolo Denti (1), Helena Rabie (2), Janice Lee (3), Helen McIlleron (1), Mark Cotton (2), Mats Karlsson (4), France Mentre’ (5), Marc Lallemant (3)
1. Division of Clinical Pharmacology, University of Cape Town 2. Department of Pediatrics and Child Health University of Stellenbosch, Tygerberg Hospital and Children’s Infectious Diseases Clinical Research Unit 3. Drugs for Neglected Diseases initiative (DNDi) 4. Uppsala University, Uppsala, Sweden 5. Inserm, IAME, UMR 1137, Université Paris Diderot, Paris, France,
Objectives: The 1st-line HIV treatment for infants includes lopinavir/ritonavir 4:1 (LPV/r). In high-burden settings, rifampicin (RIF) co-treatment for tuberculosis (TB) is common and lowers LPV exposure. Adding ritonavir (RTV) to achieve a 4:4 ratio (super-boosting) is effective, but PK was studied in 15 children only [1].
Methods: A study in South Africa compared the PK of super-boosted LPV whilst on concurrent RIF, with LPV/r alone in children weighing 3-15 kg. The objective was to prove non-inferiority defined as no more than 10% difference (with 95% confidence) in the proportion of children not achieving the therapeutic target of LPV morning Cmin>1 mg/L [2]. Blood was taken before and 1, 2, 4, 6, 10 h after dosing at 3 visits: while on LPV/r super-boosting after 1-2 months of RIF (PK1) or in the last month of RIF (PK2), and while on normal LPV/r 4:1 at 4-6 weeks after stopping RIF (PK3). Data was modelled in NONMEM 7.3. Pre-dose concentrations were modelled with a baseline approach (B2, from [3]) to handle poor information on prior doses. A structural model developed on PK1 was used to fit PK2 and PK3 data for the comparison, after adding flexibility by allowing the inclusion of separate typical values for all parameters at each PK visit and BSV and BOV whenever possible, irrespectively of statistical significance. A nonparametric bootstrap (n=500) assessed parameter uncertainty and the estimates from each iteration were used for simulations of PK profiles (n=10 000) assuming a 30% decrease in clearance overnight to account for the known diurnal variation [4]. The percentage of model-simulated morning Cmin<1 mg/L at PK2 and PK3 was compared to obtain a 95% CI and assess non-inferiority.
Results: Of 96 children enrolled, 80 completed the study. A 1-comp PK model with 1st-order absorption and elimination suitably fitted the data, allometric scaling adjusted for weight, and no effect of age could be identified. The simulated percentage of children below target with super-boosting was 7.6% (95% CI: 0.4%, 16.2%) and on normal dose was 8.8% (0.6%, 19.8%), thus resulting in a difference of -1.1% (-6.9%, 3.2%) and confirming the non-inferiority of LPV exposure during super-boosting compared with standard LPV/r.
Conclusions: LPV super-boosting during RIF treatment is as effective as standard dosing alone to achieve the therapeutic target. We suggested and successfully implemented a model-based approach to evaluate non-inferiority (or other comparisons) of PK exposure.
References:
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[2] J. Ananworanich, P. Kosalaraksa, A. Hill, U. Siangphoe, A. Bergshoeff, C. Pancharoen, C. Engchanil, K. Ruxrungtham, D. Burger, and HIV-NAT 017 Study Team, “Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children.,” Pediatr. Infect. Dis. J., vol. 24, no. 10, pp. 874–9, Oct. 2005.
[3] C. Dansirikul, H. E. Silber, and M. O. Karlsson, “Approaches to handling pharmacodynamic baseline responses,” J. Pharmacokinet. Pharmacodyn., vol. 35, no. 3, pp. 269–283, Jun. 2008.
[4] C. Zhang, P. Denti, E. Decloedt, Y. Ren, M. O. Karlsson, and H. McIlleron, “Model-based evaluation of the pharmacokinetic differences between adults and children administered lopinavir and ritonavir in combination with rifampicin,” in PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe. ISSN 1871-6032, 2012, p. Abstr 2400.
