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 Pediatric Infect Dis Soc. 31 December 2021; Volume 10 (Issue 12); 1062-1070.; DOI:10.1093/jpids/piab080
Platts-Mills JA, Houpt ER, Liu J, Zhang J, Guindo O, et al.
J Pediatric Infect Dis Soc. 31 December 2021; Volume 10 (Issue 12); 1062-1070.; DOI:10.1093/jpids/piab080
BACKGROUND
High-resolution data on the etiology of childhood diarrhea in countries with the highest burden and mortality remain sparse and are needed to inform burden estimates and prioritize interventions.
METHODS
We tested stool specimens collected between October 2014 and December 2017 from children under 2 years of age from the per-protocol population of a placebo-controlled clinical trial of a bovine rotavirus pentavalent vaccine (Rotasiil) in Niger. We tested 1729 episodes of moderate-to-severe diarrhea (Vesikari score ≥ 7) using quantitative PCR and estimated pathogen-specific burdens by age, season, severity, and trial intervention arm.
RESULTS
The 4 pathogens with the highest attributable incidence of diarrhea were Shigella (7.2 attributable episodes per 100 child-years; 95% confidence interval: 5.2, 9.7), Cryptosporidium (6.5; 5.8, 7.2), rotavirus (6.4; 5.9, 6.7), and heat-stabile toxin-producing enterotoxigenic Escherichia coli (ST-ETEC) (6.2; 3.1, 7.7). Cryptosporidium was the leading etiology of severe diarrhea (Vesikari score ≥ 11) and diarrhea requiring hospitalization. Shigella was the leading etiology of diarrhea in children 12-23 months of age but also had a substantial burden in the first year of life, with 60.5% of episodes of severe shigellosis occurring in infants. Shigella, Cryptosporidium, and ST-ETEC incidence peaked during the warmer and wetter period and coincided with peak all-cause diarrhea incidence.
CONCLUSIONS
In this high-burden setting, the leading diarrheal pathogens were Shigella, Cryptosporidium, rotavirus, and ST-ETEC, and each was disproportionately seen in infants. Vaccine development should target these pathogens, and the impact of vaccine schedule on diarrhea burden in the youngest children will need to be considered.
High-resolution data on the etiology of childhood diarrhea in countries with the highest burden and mortality remain sparse and are needed to inform burden estimates and prioritize interventions.
METHODS
We tested stool specimens collected between October 2014 and December 2017 from children under 2 years of age from the per-protocol population of a placebo-controlled clinical trial of a bovine rotavirus pentavalent vaccine (Rotasiil) in Niger. We tested 1729 episodes of moderate-to-severe diarrhea (Vesikari score ≥ 7) using quantitative PCR and estimated pathogen-specific burdens by age, season, severity, and trial intervention arm.
RESULTS
The 4 pathogens with the highest attributable incidence of diarrhea were Shigella (7.2 attributable episodes per 100 child-years; 95% confidence interval: 5.2, 9.7), Cryptosporidium (6.5; 5.8, 7.2), rotavirus (6.4; 5.9, 6.7), and heat-stabile toxin-producing enterotoxigenic Escherichia coli (ST-ETEC) (6.2; 3.1, 7.7). Cryptosporidium was the leading etiology of severe diarrhea (Vesikari score ≥ 11) and diarrhea requiring hospitalization. Shigella was the leading etiology of diarrhea in children 12-23 months of age but also had a substantial burden in the first year of life, with 60.5% of episodes of severe shigellosis occurring in infants. Shigella, Cryptosporidium, and ST-ETEC incidence peaked during the warmer and wetter period and coincided with peak all-cause diarrhea incidence.
CONCLUSIONS
In this high-burden setting, the leading diarrheal pathogens were Shigella, Cryptosporidium, rotavirus, and ST-ETEC, and each was disproportionately seen in infants. Vaccine development should target these pathogens, and the impact of vaccine schedule on diarrhea burden in the youngest children will need to be considered.