Anke E Kip1, María Del Mar Castro2, Maria Adelaida Gomez2, Alexandra Cossio2, Jan H M Schellens3,4, Jos H Beijnen1,3,4, Nancy Gore Saravia2, Thomas P C Dorlo1. 1. Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. 2. Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM), Cali, Colombia. 3. Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands. 4. Department of Clinical Pharmacology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract
Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days. Results: A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. Conclusions: The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.
Objectives:Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasispatients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days. Results: A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. Conclusions: The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasispatient population. We propose an exploratory PK target, which should be validated in a larger cohort study.
Authors: Thomas P C Dorlo; Michel J X Hillebrand; Hilde Rosing; Teunis A Eggelte; Peter J de Vries; Jos H Beijnen Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2008-02-20 Impact factor: 3.205
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Authors: A E Kip; H Rosing; M J X Hillebrand; M M Castro; M A Gomez; J H M Schellens; J H Beijnen; T P C Dorlo Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2015-06-24 Impact factor: 3.205
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Authors: Thomas P C Dorlo; Alwin D R Huitema; Jos H Beijnen; Peter J de Vries Journal: Antimicrob Agents Chemother Date: 2012-05-14 Impact factor: 5.191
Authors: Linda G Franken; Marith I Francke; Louise M Andrews; Ron H N van Schaik; Yi Li; Lucia E A de Wit; Carla C Baan; Dennis A Hesselink; Brenda C M de Winter Journal: Eur J Drug Metab Pharmacokinet Date: 2022-04-20 Impact factor: 2.569
Authors: Semra Palić; Anke E Kip; Jos H Beijnen; Jane Mbui; Ahmed Musa; Alexandra Solomos; Monique Wasunna; Joseph Olobo; Fabiana Alves; Thomas P C Dorlo Journal: J Antimicrob Chemother Date: 2020-11-01 Impact factor: 5.790