Pharmacokinetic considerations in the use of antivirals in neonates

Abstract

Introduction: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children.

Areas covered: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates.

Expert opinion: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.

Keywords:

• :antiviral drugs
• enteroviruses
• herpes viruses
• HIV
• influenza
• neonates
• pharmacokinetics of antiviral drugs in neonates

Article highlights.

• Neonates are predisposed to viral infections due to inability to mount protective antiviral responses. The majority of viral infections in neonates are associated with significant rates of mortality and morbidity, can lead to permanent organ and system dysfunctions.

• Acyclovir is used to treat neonatal HSV infections carrying a high risk of CNS complications. Dosing regimens based on PMA and GA help to consistently achieve or exceed recommended minimum concentrations and may lead to improved clinical outcomes. Acyclovir use is associated with an increased risk of neutropenia.

• IV Ganciclovir and oral valganciclovir (pro-drug of ganciclovir) demonstrate excellent activity toward CMV, but their use is associated with a high risk of neutropenia. The PK profile of valganciclovir is well described by a one-compartment model with body weight as the most important covariate for dosing. In circumstances where the treatment duration is expected to be prolonged, the use of valganciclovir is recommended.

• Pharmacokinetics of NRTIs vary. Recommended doses for the combination of zidovudine and lamivudine are dependent on GA at birth as well as postnatal age, as drug exposure appears dependent on the maturation of renal and hepatic systems. The disposition of tenofovir and emtricitabine do not differ significantly between neonates and adults, however, these drugs are not yet approved for use in neonates. Limited data demonstrate the potential for differences in cellular transport and phosphorylation of NRTIs to the pharmacologically active form in neonates versus adults.

• Clearance of nelfinavir varies significantly depending on age, and is highest in children < 2 years of age. Therapeutic drug monitoring should be utilized to ensure adequate nelfinavir exposure in HIV-infected neonates within first weeks of life.

• Oseltamivirat is the only approved drug for treating influenza in children 2 weeks −12 month. The dose 3 mg/kg/dose twice daily delivers acceptable drug exposure without increased risk of treatment failure in neonates.

• Pleconaril may be considered for the treatment of neonatal enterovirus infections; however, the pharmacokinetics of pleconaril do not exhibit dose proportionality among neonates. Furthermore, pleconaril is only available for use in clinical trials and not been FDA approved nor is it available for compassionate use.

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Declaration of interest

C Stockmann is supported by the American Foundation for Pharmaceutical Education’s Clinical Pharmaceutical Sciences Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.