Luka Verrest (1), Ignace Roseboom (1), Monique Wasunna (2), Jane Mbui (3), Ahmed Musa (4), Alwin Huitema (1,5,6), Alexandra Solomos (7), Fabiana Alves (7), Thomas Dorlo (1)
(1) Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, (2) Drugs for Neglected Diseases initiative - Africa, Nairobi, Kenya, (3) Kenya Medical Research Insititute, Nairobi, Kenya, (4) Institute of Endemic Diseases, University of Khartoum, Sudan, (5) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, The Netherlands, (6) Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, (7) Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
Objectives: In Eastern Africa, effective, safe and affordable combination treatments for visceral leishmaniasis (VL) are still lacking. Geographical variability in paromomycin (PM) pharmacokinetics in Eastern Africa was previously observed, but drug exposure could not be related to treatment outcome [1]. Recently, 14- & 28-day combination regimens of PM plus allometric MF were evaluated in Eastern Africa [2]. An increase in PM exposure both with age and over time (D14 versus D1 of treatment) were observed. In the current pharmacokinetic analysis, we aimed to characterize the pharmacokinetics of PM in these combination regimens, to evaluate adequacy of PM exposure in children and adults, to explore geographical pharmacokinetic differences, and to explain the change in PK by renal function or hematological markers.
Methods: PM PK data was available from a multi-centre randomized controlled trial in VL patients from Kenya and Sudan [2]. Intramuscular PM (20 mg/kg for 14 days) plus oral miltefosine (MF) (allometric dose for 14 days (Arm 1) or 28 days (Arm 2)) was compared to PM plus intravenous sodium stibogluconate (SSG) combination therapy (PM 15 mg/kg/day and SSG 20 mg/kg/day for 17 days). Plasma samples were obtained frequently at Day 1 and Day 14, and PM concentrations were obtained using LC-MS/MS [3]. A population PK model was developed using NONMEM (v 7.5). A total of 254 samples from 26 patients were included in the analysis. The previously developed PM PK model in Eastern African and Indian VL patients was used as the starting model [1], and included covariates were re-evaluated. To explain variability in PM PK as well the change in PK over time, the covariates age, country, and the time-varying covariates creatinine, eGFR, albumin, and white blood cells were tested.
Results: A two-compartment model with first-order absorption best described PM in plasma. Typical parameter estimates (RSD) were an apparent oral clearance (CL/F) of 3.13 L/h (6%), central volume of distribution (Vc/F) of 10.3 L (4%), inter-compartmental clearance (Q/F) of 0.268 L/h (9%), peripheral volume of distribution (Vp/F) of 8.01 L (30%), and an absorption rate constant (ka/F) of 2.29 h-1(11%). Body weight was allometrically included on CL, Q, Vc and Vp, with fixed powers of 0.75 and 1.00, respectively. Between-subject variability (BSV) was included on clearance (23.1%). Time varying creatinine reduced the BSV in CL from 55.1% to 24.6%. A decrease in clearance over time was observed, largely explained by the increase in white blood cells over time. decrease in clearance over time was observed, which will be further explored. Age and country could not further explain variability in any of the PK parameters. D14 AUC0-24 of PM was higher compared to previous studies, suggesting adequate PM exposure.
Conclusions: The developed PK model of PM in Kenyan and Sudanese VL patients gives insight into the PK in different populations, and changes in PK between start and end of treatment. Parameters were comparable to the previous PM PK model. A relationship of serum creatinine and clearance was identified. The relationship of age with clearance was not identified this time, but the decrease in clearance over time was also present in this population, which correlated to the increase in white blood cells. In the future, these covariate relationships will be further explored. In the final model, no significant PK differences between countries were identified, indicating no geographical differences that are not explained by the included covariates.
References:
[1] Verrest L, Wasunna M, Kokwaro G, et al. Geographical Variability in Paromomycin Pharmacokinetics Does Not Explain Efficacy Differences between Eastern African and Indian Visceral Leishmaniasis Patients. Clin Pharmacokinet. 2021 Nov;60(11):1463-1473
[2] Musa AM, Mbui J, Mohammed R, et al. Paromomycin and miltefosine combination as an alternative to treat patients with visceral leishmaniasis in Eastern Africa: a randomized, multi-country controlled trial. (forthcoming)
[3] Roseboom IC, Thijssen B, Rosing H, Mbui J, Beijnen JH, Dorlo TPC. Highly sensitive UPLC-MS/MS method for the quantification of paromomycin in human plasma. J Pharm Biomed Anal. 2020 Jun 5;185:113245
Reference: PAGE 30 (2022) Abstr 10215 [www.page-meeting.org/?abstract=10215]
Poster: Drug/Disease Modelling - Infection