A.E. Kip (1,2), M.A. Gomez (3), M.M. Castro (3), A. Cossio (3), J.H.M. Schellens (2,4), J.H. Beijnen (1,2,4), N.G. Saravia (3), T.P.C. Dorlo (2,5)
(1) Dept. of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands, (2) Div. of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands, (3) Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM), Cali, Colombia, (4) Dept. of Clinical Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands, (5) Dept. Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Miltefosine is the most important oral drug against cutaneous leishmaniasis (CL). Though Leishmania parasites reside within macrophages, the intracellular PK of miltefosine has not been studied previously. Our aim was to develop a population PK model describing both plasma and intracellular miltefosine PK in CL patients. This model will contribute to the understanding of the relation between drug exposure and treatment outcome and provides bases for alternative dosing regimens.
Methods: Fifty-one Colombian CL patients (29 children 2-12y, 22 adults ≥18y), receiving a 28-day 2.5 mg/kg/day miltefosine treatment, were included in the model. 338 plasma and 194 peripheral blood mononuclear cell (PBMC) samples were collected and analyzed with LC-MS/MS [1,2]. A population PK model was developed with NONMEM (v7.3), with both plasma and PBMC data. Weight, age, gender, fat-free mass (FFM), ethnicity and treatment center were evaluated as covariates. Precision and predictive performance of the model were assessed by bootstrap and visual predictive checks. A previously developed allometric dosing algorithm [3] was evaluated for its effect on drug exposure by simulating PK curves (1,000 simulations/individual) and predicting AUC0-∞. Values are reported as mean±SD.
Results: Miltefosine accumulates to a higher end-of-treatment steady-state concentration in PBMCs (75.0±65.6 µg/mL) than in plasma (26.1±6.8 µg/mL). A three-compartment model with intracellular miltefosine accumulation within the central compartment was most adequate. Distribution of miltefosine into PBMCs was best described with an intracellular to plasma ratio (2.17, RSE 29%) plus an intracellular distribution rate constant (1.15 day-1, RSE 14%). FFM was a significant covariate on clearance and Vd. Addition of a maturation factor in the FFM calculation [4] significantly improved the model (ΔOFV -7.46). With linear dosing, children only reach 82% of adult AUC0-∞ in plasma (813±159 v. 986±184 µg·day/mL) and PBMCs (1831±652 v. 2225±785 µg·day/mL). Simulating allometric dosing, the AUC0-∞ in children increased to 964±169 µg·day/mL in plasma and 2173±751 µg·day/mL in PBMCs.
Conclusions: The PK of miltefosine in CL patients conforms to a three-compartment model with intracellular accumulation of the drug. Simulation of an allometric dosing shows an increase in drug exposure for pediatric CL patients, suggesting a possible improvement in miltefosine treatment outcome in children.
References:
[1] Dorlo TP, Hillebrand MJ, Rosing H, Eggelte TA, de Vries PJ, Beijnen JH. Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry. J Chrom B (2008) 865(1-2): 55–62.
[2] Kip AE, Rosing H, Hillebrand MJ, Castro MM, Gomez MA, Schellens JH, Beijnen JH, Dorlo TP. Quantification of miltefosine in peripheral blood mononuclear cells by high-performance liquid chromatography-tandem mass spectrometry. J Chrom B (2015) 998: 57-62
[3] Dorlo TP, Huitema AD, Beijnen JH, de Vries PJ. Optimal dosing of miltefosine in children and adults with visceral leishmaniasis. Antimicrob Agents Chemother (2012) 56(7): 3864-72.
[4] Al-Sallami HS, Goulding A, Grant A, Taylor R, Holford N, Duffull SB. Prediction of Fat-Free Mass in Children. Clin Pharmacokinet (2015) 54(11):1169-78.
Registration number in Clinicaltrials.gov: NCT01462500 Funding: COLCIENCIAS (250-2010); COLCIENCIAS (0040-2012) and Fogarty International Center of the National Institutes of Health under Training Award number D43TW006589.
Reference: PAGE 25 (2016) Abstr 5904 [www.page-meeting.org/?abstract=5904]
Poster: Drug/Disease modeling - Infection