Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis

Abstract

Objectives: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.

Methods: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.

Results: Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults.

Conclusions: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.

Figure 1.

Paromomycin plasma concentrations included in the pharmacokinetic analysis, stratified by sampling day. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Miltefosine plasma concentrations included in the pharmacokinetic analysis, stratified by treatment arm. PM + MF14D, paromomycin 14 days + miltefosine 14 days; PM + MF28D, paromomycin 14 days + miltefosine 28 days. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

GoF plots for the final paromomycin pharmacokinetic model. Observed versus population-predicted paromomycin concentrations; observed versus individually predicted paromomycin concentrations; conditional weighted residuals (CWRES) versus population predicted concentrations; and CWRES versus time after last dose.

Figure 4.

Prediction-corrected VPC of the final paromomycin pharmacokinetic model. The solid lines represent the median of the observed values, and the dashed lines the 20th and 80th percentiles of the observed values. The dark and light areas indicate the 90% CIs of the simulated median and percentiles, respectively, based on 1000 simulations. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

GoF plots for the final miltefosine pharmacokinetic model, coloured by treatment arm. Observed versus population-predicted paromomycin concentrations; observed versus individually predicted paromomycin concentrations; conditional weighted residuals (CWRES) versus population-predicted concentrations; and CWRES versus time after last dose. Blue dots, treatment arm 1 (miltefosine dosing for 14 days); grey dots, treatment arm 2 (miltefosine dosing for 28 days). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 6.

Prediction-corrected VPC of the final miltefosine pharmacokinetic model. The solid lines represent the median of the observed values, the dashed lines the 5th and 95th percentiles of the observed values. The dark and light areas indicate the 90% CIs of the simulated median and percentiles, respectively, based on 500 simulations. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 7.

Paromomycin exposure (AUC_0–24) at last day of treatment (Day 14) in paediatrics (≤12 years) and adults (>12 years), compared with previously observed paromomycin exposure (Day 21) in adult Sudanese and Kenyan patients receiving 20 mg/kg/day paromomycin for 21 days (the marked area represents the IQR). One outlier patient with an extremely high AUC_0–24 of 2388 µg × h/mL is not shown in this figure. This patient developed ototoxicity due to renal failure.

Figure 8.

Cumulative miltefosine exposure until Day 28 (AUC_D0–28) in paediatrics (≤12 years) and adults (>12 years), receiving 14 days of miltefosine (PM + MF14D, left panel) and 28 days of miltefosine (PM + MF28D, right panel), compared with previously observed Day 28 miltefosine exposure in adult Eastern African patients receiving miltefosine allometric dosing for 28 days (the marked area represents the IQR). One outlier patient with an AUC_D0–28 of 2106 µg × day/mL (PM + MF14D, 10 years old) is not shown in this figure.

Figure 9.

Miltefosine T_>EC90 in paediatrics (≤12 years) and adults (>12 years), receiving 14 days of miltefosine (PM + MF14D, left panel) and 28 days of miltefosine (PM + MF28D, right panel), compared with previously observed T_>EC90 in adult Eastern African patients receiving miltefosine conventional dosing for 28 days (the marked area represents the IQR).