Simultaneous population pharmacokinetic modelling of plasma and intracellular PBMC miltefosine concentrations in New World cutaneous leishmaniasis and exploration of exposure-response relationships

The Journal of Antimicrobial Chemotherapy
Anke E KipThomas P C Dorlo

Abstract

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. 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. 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-...Continue Reading

References

Sep 24, 2005·Clinical Pharmacokinetics·Sarayut JanmahasatianBruce Green
Jan 26, 2007·Pharmaceutical Research·Cécile MénezGillian Barratt
Mar 8, 2008·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Thomas P C DorloJos H Beijnen
Jun 4, 2008·Antimicrobial Agents and Chemotherapy·Thomas P C DorloPeter J de Vries
Jan 22, 2010·The Journal of Antimicrobial Chemotherapy·Karin SeifertSimon L Croft
Oct 12, 2011·Antimicrobial Agents and Chemotherapy·Maria C KjellssonVéronique Dartois
Apr 21, 2012·Journal of Clinical Microbiology·Olga FernándezNancy Gore Saravia
May 16, 2012·Antimicrobial Agents and Chemotherapy·Thomas P C DorloPeter J de Vries
Jul 27, 2012·The Journal of Antimicrobial Chemotherapy·Thomas P C DorloPeter J de Vries
Jan 21, 2014·The Journal of Infectious Diseases·Thomas P C DorloAlwin D R Huitema
May 6, 2015·Clinical Pharmacokinetics·Hesham Saleh Al-SallamiStephen Brent Duffull
Jul 15, 2015·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·A E KipT P C Dorlo

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Citations

Feb 27, 2020·Clinical Pharmacokinetics·Valentin Al Jalali, Markus Zeitlinger
Aug 21, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·María Adelaida GómezNancy Gore Saravia
Jul 1, 2021·The Journal of Antimicrobial Chemotherapy·Adrien ContejeanCaroline Charlier
Oct 26, 2021·International Journal of Antimicrobial Agents·Semra PalićThomas P C Dorlo

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