Journal Article > CommentaryFull Text
J Infect Dis. 16 December 2024; Volume 230 (Issue 6); e1375-1384.; DOI:10.1093/infdis/jiae413
Chu WY, Verrest L, Younis BM, Musa AM, Mbui J, et al.
J Infect Dis. 16 December 2024; Volume 230 (Issue 6); e1375-1384.; DOI:10.1093/infdis/jiae413
Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.
Conference Material > Poster
Optimizing nutrient supplementation among pregnant and reproductive age women in Kenya (VIRUTUBISHO)
Talbert A, Mwangome M, Berkley JA
MSF Paediatric Days 2024. 3 May 2024; DOI:10.57740/bLKnp9
Journal Article > ResearchFull Text
Clin Pharmacol Ther
Clinical Pharmacology and Therapeutics. 1 May 2024; Volume 115 (Issue 5); 1105-1113.; DOI:10.1002/cpt.3174
Chupradit S, Wamalwa DC, Maleche‐Obimbo E, Kekitiinwa AR, Mwanga‐Amumpaire J, et al.
Clin Pharmacol Ther
Clinical Pharmacology and Therapeutics. 1 May 2024; Volume 115 (Issue 5); 1105-1113.; DOI:10.1002/cpt.3174
Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed‐effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one‐compartment model with first‐order absorption (incorporating a lag‐time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation‐predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.
Journal Article > ResearchFull Text
J Pediatric Infect Dis Soc. 5 October 2023; Volume 12 (Issue 11); 574-580.; DOI:10.1093/jpids/piad082
Chupradit S, Wamalwa DC, Maleche-Obimbo E, Kekitiinwa AR, Mwanga-Amumpaire J, et al.
J Pediatric Infect Dis Soc. 5 October 2023; Volume 12 (Issue 11); 574-580.; DOI:10.1093/jpids/piad082
BACKGROUND
The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing < 14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands.
METHODS
Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0–24) of 6.4–50.4 mg h/L were used as targets.
RESULTS
Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0–24.9 kg, but children weighing 3–5.9 kg were predicted to be overexposed.
CONCLUSIONS
Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3–5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.
The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing < 14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands.
METHODS
Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0–24) of 6.4–50.4 mg h/L were used as targets.
RESULTS
Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0–24.9 kg, but children weighing 3–5.9 kg were predicted to be overexposed.
CONCLUSIONS
Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3–5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.
Journal Article > ResearchFull Text
J Antimicrob Chemother. 20 September 2023; Online ahead of print; dkad286.; DOI:10.1093/jac/dkad286
Verrest L, Roseboom IC, Wasunna M, Mbui J, Njenga SN, et al.
J Antimicrob Chemother. 20 September 2023; Online ahead of print; dkad286.; DOI:10.1093/jac/dkad286
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.
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.
Conference Material > Video
Coldiron ME
MSF Scientific Days International 2020: Research. 13 May 2020
Journal Article > ResearchFull Text
Clin Pharmacol Ther
Clinical Pharmacology and Therapeutics. 25 October 2019; Volume 107 (Issue 5); 1179-1188.; DOI:10.1002/cpt.1707
Ding J, Coldiron ME, Assao B, Guindo O, Blessborn D, et al.
Clin Pharmacol Ther
Clinical Pharmacology and Therapeutics. 25 October 2019; Volume 107 (Issue 5); 1179-1188.; DOI:10.1002/cpt.1707
Poor adherence to seasonal malaria chemoprevention (SMC) might affect the protective effectiveness of SMC. Here, we evaluated the population pharmacokinetic properties of amodiaquine and its active metabolite, desethylamodiaquine, in children receiving SMC under directly observed ideal conditions (n = 136), and the adherence of SMC at an implementation phase in children participating in a case-control study to evaluate SMC effectiveness (n = 869). Amodiaquine and desethylamodiaquine concentration-time profiles were described simultaneously by two-compartment and three-compartment disposition models, respectively. The developed methodology to evaluate adherence showed a sensitivity of 65-71% when the first dose of SMC was directly observed and 71-73% when no doses were observed in a routine programmatic setting. Adherence simulations and measured desethylamodiaquine concentrations in the case-control children showed complete adherence (all doses taken) in < 20% of children. This result suggests that more efforts are needed urgently to improve the adherence to SMC among children in this area.
Journal Article > ResearchFull Text
Antibiotics. 18 June 2021; Volume 10 (Issue 6); 739.; DOI:10.3390/antibiotics10060739
Rao PS, Moore CC, Mbonde AA, Nuwagira E, Orikiriza P, et al.
Antibiotics. 18 June 2021; Volume 10 (Issue 6); 739.; DOI:10.3390/antibiotics10060739
Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0-24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0-24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500-3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed.
Conference Material > Slide Presentation
Coldiron ME
MSF Scientific Days International 2020: Research. 13 May 2020
Conference Material > Abstract
Ding J, Coldiron ME, Assao B, Guindo O, Blessborn D, et al.
MSF Scientific Days International 2020: Research. 20 May 2020
INTRODUCTION
Seasonal malaria chemoprevention (SMC) has been widely implemented by MSF in the African Sahel. It consists of monthly courses of antimalarial drugs during the high-risk season. A single dose of sulfadoxine-pyrimethamine (SP) and a dose of amodiaquine (AQ) are administered by a health worker, and doses of AQ are administered by caregivers at home on the following two days. Poor adherence to AQ might reduce the protective effectiveness of SMC. In an area of Niger where MSF was concerned about the effectiveness of SMC, we performed a study to describe the population pharmacokinetic (PK) properties of AQ when administered as part of SMC. These data were used to develop models describing adherence to SMC among children participating in a case-control study performed in the same area.
METHODS
A convenience sample of 165 children aged 3-59 months was enrolled in Magaria, Niger, in November 2016. All three doses of SMC were administered at home by nurses, and then blood samples were drawn in six predefined sampling windows over the following six weeks. Drug concentrations were determined using a liquid chromatography tandem mass spectrometry-based assay. Concentration-time data were evaluated simultaneously using nonlinear mixed-effects modelling in the software NONMEM (Icon, Hanover, USA). In the case-control study, one-half (n=297) of cases and their 859 healthy village- and age-matched controls were randomly selected to be analysed for drug concentrations and adherence.
ETHICS
This study was approved by the MSF Ethical Review Board and the Comité Consultatif National d’Éthique of Niger.
RESULTS
We used two-compartment and three-compartment disposition models respectively to describe AQ and desethylamodiaquine (DEAQ) concentration-time profiles. This method for evaluation of adherence showed a sensitivity of 65-71%, when the first dose of SMC was directly observed by a health worker. Among case-control study participants, modelled adherence simulations and measured DEAQ concentrations showed poor adherence. Using the optimal model, only 7% of cases and 8% of controls had complete adherence to AQ. Even when using the most conservative cut-offs in the model (5th percentile of DEAQ concentration), only 10% of cases and 17% of controls had complete adherence.
CONCLUSION
To our knowledge, this is the first description of the population pharmacokinetics of AQ when used in the setting of SMC; the model was robust and showed good predictive performance. Despite community engagement efforts, adherence to SMC was very poor in this setting. Efforts to improve adherence are urgently needed, both to protect children against malaria and to prevent emergence of resistance to SP and AQ.
CONFLICTS OF INTEREST
None declared.
Seasonal malaria chemoprevention (SMC) has been widely implemented by MSF in the African Sahel. It consists of monthly courses of antimalarial drugs during the high-risk season. A single dose of sulfadoxine-pyrimethamine (SP) and a dose of amodiaquine (AQ) are administered by a health worker, and doses of AQ are administered by caregivers at home on the following two days. Poor adherence to AQ might reduce the protective effectiveness of SMC. In an area of Niger where MSF was concerned about the effectiveness of SMC, we performed a study to describe the population pharmacokinetic (PK) properties of AQ when administered as part of SMC. These data were used to develop models describing adherence to SMC among children participating in a case-control study performed in the same area.
METHODS
A convenience sample of 165 children aged 3-59 months was enrolled in Magaria, Niger, in November 2016. All three doses of SMC were administered at home by nurses, and then blood samples were drawn in six predefined sampling windows over the following six weeks. Drug concentrations were determined using a liquid chromatography tandem mass spectrometry-based assay. Concentration-time data were evaluated simultaneously using nonlinear mixed-effects modelling in the software NONMEM (Icon, Hanover, USA). In the case-control study, one-half (n=297) of cases and their 859 healthy village- and age-matched controls were randomly selected to be analysed for drug concentrations and adherence.
ETHICS
This study was approved by the MSF Ethical Review Board and the Comité Consultatif National d’Éthique of Niger.
RESULTS
We used two-compartment and three-compartment disposition models respectively to describe AQ and desethylamodiaquine (DEAQ) concentration-time profiles. This method for evaluation of adherence showed a sensitivity of 65-71%, when the first dose of SMC was directly observed by a health worker. Among case-control study participants, modelled adherence simulations and measured DEAQ concentrations showed poor adherence. Using the optimal model, only 7% of cases and 8% of controls had complete adherence to AQ. Even when using the most conservative cut-offs in the model (5th percentile of DEAQ concentration), only 10% of cases and 17% of controls had complete adherence.
CONCLUSION
To our knowledge, this is the first description of the population pharmacokinetics of AQ when used in the setting of SMC; the model was robust and showed good predictive performance. Despite community engagement efforts, adherence to SMC was very poor in this setting. Efforts to improve adherence are urgently needed, both to protect children against malaria and to prevent emergence of resistance to SP and AQ.
CONFLICTS OF INTEREST
None declared.
