Louvina E. van der Laan1,2,, Anthony J. Garcia-Prats2, H. Simon Schaaf2, Maxwell Chirehwa1, Jana L. Winckler2, Heather R. Draper2, Lubbe Wiesner1, Jennifer Norman1, Helen McIlleron1, Peter R Donald2 , Anneke C. Hesseling2 , Paolo Denti1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. 2 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Objectives: Para-aminosalicylic acid (PAS) remains an important drug in the management of multidrug-resistant tuberculosis (MDR-TB). PAS prevention of resistance in companion drugs is dosage related and at higher concentrations PAS may exhibit significant bactericidal activity in addition to bacteriostatic properties. PAS is mainly (80%) renally eliminated. Optimal dosing in children is uncertain, specifically for newer, more tolerable slow-release granule preparations. We aim to describe the pharmacokinetics of the current slow-release PAS formulation in children treated for MDR-TB, to identify any important covariates and to optimise drug dosing and exposure through simulations.
Methods: South African children, established on a PAS-containing MDR-TB regimen (including combinations of levofloxacin/moxifloxacin/ofloxacin, linezolid, clofazimine, terizidone, pyrazinamide, ethambutol, ethionamide, high-dose isoniazid, amikacin and capreomycin) were included. PAS was dosed at 150-200 mg/kg twice-daily according to the dose used for routine care at the time (2012). The formulation used was the slow-release granule formulation by PASER®(1). The granules were administered with acidic food as per administration guidelines(1). Intensive pharmacokinetic sampling was completed at pre-dose and at 1, 2, 4, 8, and 11 h after dosing. The samples were analysed using LC MS/MS detection, LLOQ 0.391 mg/L. NONMEM 7.4.4 with FOCE-I was used to develop the population pharmacokinetic model and PsN, Pirana, R, and Xpose were used in the model building process for data exploration, visualization and creation of diagnostics (2). Allometric scaling (3) was used to account for the effect of body size, using either total body weight or fat-free mass (4). Age was tested using a sigmoid Emax maturation model (3, 5). BLQ values were handled by the M6 method from Beal (6) and for all imputed values the additive error was inflated by LLOQ/2. Finally, model-based simulations were completed to evaluate the current WHO (2019)(7) (200-300 mg/kg/day given as a once- or twice-daily dose) weight-band doses against adult target (peak PAS concentrations of 50-100 mg/L) attainments.
Results: Of 27 children included, the median (range) age and weight were 3.87 (0.58-13.7) years, and 13.3 (7.15-30.5) kg; 4-children (14.8 %) were HIV-positive (3 lopinavir/ritonavir- and 1 efavirenz-based regimen). PAS followed one-compartment kinetics with first-order elimination and transit-compartment absorption. Allometric scaling using body weight was included as it is strongly advocated for use in paediatric populations (3, 5, 8), although the model showed no significant improvement after its inclusion. Use of fat-free mass instead of total body weight did not provide further benefit regarding model fit. Maturation parameters could not be robustly identified, possible because only two were below 1-year of age, so Bayesian priors based on previously reported maturation of renal function (9), with 20% uncertainty, were included in the model to improve simulation estimates in younger children. The typical clearance in a 13-kg child was 9.36 L/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz; this was retained in the model, as this interaction was previously reported in adults (10). No effect of renal function, sex, ethnicity, nutritional status, HIV status, other antiretrovirals (lamivudine, abacavir, lopinavir/ritonavir) or MDR-TB drugs was detected. The model detected very large (65,9%) inter-occasion variability (IOV) in bioavailability. Simulations revealed that peak PAS concentrations of 50-100 mg/L, were achieved only in children receiving PAS at the higher WHO dose range of 300 mg/kg in a once-daily dose.
Conclusions: We developed a model adequately describing concentrations of PAS in children receiving the slow-release PAS formulation. We detected a large IOV in bioavailability, likely related to the slow release of the granular formulation in the small intestine. The PAS from the granules is mainly absorbed in the small intestine, since the acid-resistant coating protects against degradation in the stomach(1). We confirmed increased clearance following efavirenz co-administration, likely related to N-acetyltransferase-1 (NAT-1) or NAT-2 induction by efavirenz. For optimized PAS treatment, children should be dosed at the higher bound of the WHO range, with a single- and not divided-daily dose.
References:
[1] PASER® GRANULES(Aminosalicylic Acid Delayed-Release Granules). https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=6f2753dc-5f.
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[4] Al-Sallami HS, Goulding A, Grant A, Taylor R, Holford N, Duffull SB. 2015. Prediction of fat-free mass in children. Clin Pharmacokinet 54:1169–1178.
[5] Anderson BJ, Holford NHG. 2009. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet 24:25–36.
[6] Beal SL. 2001. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28:481–504.
[7] WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
[8] Anderson BJ, Holford NHG. 2008. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332.
[9] Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NHG. 2009. Human renal function maturation: A quantitative description using weight and postmenstrual age. Pediatr Nephrol 24:67–76.
[10] De Kock L, Sy SKBB, Rosenkranz B, Diacon AH, Prescott K, Hernandez KR, Yu M, Derendorf H, Donald PR. 2014. Pharmacokinetics of para-aminosalicylic acid in HIV-uninfected and HIV-coinfected tuberculosis patients receiving antiretroviral therapy, managed for multidrug-resistant and extensively drug-resistant tuberculosis. Antimicrob Agents Chemother 58:6242–6250.
Reference: PAGE 29 (2021) Abstr 9787 [www.page-meeting.org/?abstract=9787]
Poster: Drug/Disease Modelling - Paediatrics