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Antiretroviral pharmacokinetics in the paediatric population: a review
Jennifer R King1, David W Kimberlin, Grace M Aldrovandi
1Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
Insights
Paediatric pharmacotherapy for human immunodeficiency virus (HIV) requires consideration of growth and development. Unique physiological factors in children impact antiretroviral drug absorption, affecting treatment efficacy and safety.
Area of Science:
- Pharmacology
- Paediatric Medicine
- Infectious Diseases
Background:
- Children with human immunodeficiency virus (HIV) present unique pharmacotherapeutic challenges.
- Growth and development significantly alter drug absorption, distribution, metabolism, and excretion in paediatric patients.
- Immature physiological systems (renal, hepatic) and developmental stages lead to variable antiretroviral drug exposure in children.
Purpose of the Study:
- To highlight the critical need to consider paediatric-specific pharmacokinetic characteristics in HIV treatment.
- To underscore the impact of developmental variations on antiretroviral drug disposition and potential toxicity in children.
- To emphasize the limited pharmacokinetic data available for antiretrovirals in paediatric populations.
Main Methods:
- Review of existing literature on paediatric antiretroviral pharmacokinetics.
- Analysis of pharmacokinetic differences in nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) across paediatric age groups.
- Identification of knowledge gaps in paediatric antiretroviral drug assessment.
Main Results:
- Significant pharmacokinetic variability exists for NRTIs (e.g., zidovudine, didanosine, stavudine, lamivudine) due to age-related differences in hepatic and renal function.
- Limited data available for NNRTIs in children, with observed decreased nevirapine elimination in neonates and noted efavirenz differences in various age groups.
- Protease inhibitors exhibit altered metabolism via the immature cytochrome P450 system in younger children, increasing toxicity risk.
Conclusions:
- Paediatric-specific pharmacokinetic data for antiretrovirals are scarce, leading to suboptimal dosage selection.
- Antiretroviral therapy in children requires careful consideration of developmental pharmacokinetics to prevent treatment failure and toxicity.
- Early assessment of antiretroviral pharmacokinetics during drug development is crucial for optimizing paediatric HIV treatment.
Abstract:
Characteristics unique to paediatric pharmacotherapy should be considered when treating children infected with human immunodeficiency virus (HIV). Processes of growth and development in the paediatric patient can significantly affect drug absorption and disposition. Immature renal function, altered hepatic enzyme activity and differences in drug absorption lead to variations in systemic exposure of antiretrovirals among children. Paediatric patients are also subject to unique circumstances that may prevent adherence to antiretroviral regimens. The pharmacokinetics of nucleoside reverse transcriptase inhibitors differ significantly among preterm infants, full-term infants and older children. Decreased hepatic glucuronidation activity in neonates results in pharmacokinetic differences in zidovudine disposition when compared with older children. Didanosine, stavudine and lamivudine are renally eliminated, thus resulting in differences among young children with immature renal function. Pharmacokinetic data for non-nucleoside reverse transcriptase inhibitors in children are limited. Decreased elimination of nevirapine among neonates has been observed, primarily due to decreased enzymatic activity. Pharmacokinetic differences across age groups have been noted for efavirenz, but no formal assessments have been conducted in children weighing less than 10kg. Protease inhibitors are metabolised by the cytochrome P450 enzyme system, which is not fully developed in younger children. Decreased metabolism can result in elevated plasma concentrations, thereby increasing the chance of toxicity. Unfortunately, few studies exist evaluating the pharmacokinetics of antiretrovirals in children. As a result, dosage selection of antiretrovirals in children often occurs without adequate data. As the life expectancy of HIV-infected children increases, use of antiretrovirals to prevent disease progression also increases. If prevention of treatment failure continues to be the goal of antiretroviral therapy, the pharmacokinetics of antiretrovirals in children need to be assessed early in the drug development process.