Review of Tenofovir Use in HIV-Infected Children
Review of Tenofovir Use in HIV-Infected Children
Data from the phase I/II dose-escalation study of once daily TDF among HIV-infected adults showed a dose-related effect on viral load and demonstrated that 300 mg is the most appropriate dose. A comparison of pharmacokinetic parameters in adult and pediatric studies is shown in Table 1. The first pharmacokinetic study in 18 HIV-infected US children ages 6–16 years found that a median TDF dose of 208 mg/m body surface area (which fell within ±5% of the dose calculated as 8 mg/kg body weight) resulted in lower area under curve (AUC) and the maximum level after the dose was administered, compared to these parameters in adults taking the 300 mg dose. In 40 Thai children ages 3.1–17.7 years (median 12.2) who received TDF at the dose of 7.6 (±1.2) mg/kg or 215 (±26) mg/m, in combination with lamivudine and efavirenz, the 90% confidence interval (CI) for the geometric mean AUC fell within ±20% of that reported in adults and parameters did not differ between those above or below age 12 years. When combined with the results of the previous modeling study which documented higher intracellular TFV-DP concentration in children and adolescents aged between 8.6 and 17 years, drug exposure is expected to be appropriate at the approved dose.
Drug interactions between TDF and protease inhibitors(PIs) have been well documented. In general, TDF decreases drug exposure of atazanavir, while boosted PIs increase drug exposure of TDF. Thus, to reduce the risk of subtherapeutic concentration, atazanavir must always be boosted with ritonavir (atazanavir/r) when used concomitantly with TDF. A study of US children (median age 14 years) demonstrated a trend toward a decrease in TFV renal clearance in children who received TDF with atazanavir/r. However, the 90% CIs of AUC and C24 of TFV overlapped with the target range for all combinations. The recently published population pharmacokinetics data in 93 HIV-infected French children showed that ritonavir-boosted lopinavir (lopinavir/r) decreased TFV clearance by 25%, leading the authors to propose using a lower dose of TDF when coadministered with lopinavir/r (150 mg for 20–40 kg, 225 mg for >40–55 kg and 300 mg for >55 kg body weight). However, that dosing recommendation has not been adopted in the current US or World Health Organization guidelines. In contrast, some studies in youth reported low TFV AUC even when TDF was used with boosted-PI. More research on drug interactions of TDF with boosted PIs is needed to identify the optimal TDF dose in children.
Clinically significant interactions have been reported for TDF with ARVs other than PIs. When coadministered with TDF, didanosine plasma concentration and risk of didanosine toxicities are increased; therefore, TDF and didanosine should generally not be used concomitantly. Based on a pharmacokinetic study showing comparable didanosine AUC among adults who received 250 mg of enteric-coated didanosine tablet in combination with TDF and those who received a standard dose 400 mg didanosine without TDF, the dose of didanosine should be reduced from 400 to 250 mg when coadministered with TDF in adults weighing >60 kg. There is no similar information available in children. Prescription of TDF with didanosine should be avoided.
Pharmacokinetic Data and Drug Interactions
Data from the phase I/II dose-escalation study of once daily TDF among HIV-infected adults showed a dose-related effect on viral load and demonstrated that 300 mg is the most appropriate dose. A comparison of pharmacokinetic parameters in adult and pediatric studies is shown in Table 1. The first pharmacokinetic study in 18 HIV-infected US children ages 6–16 years found that a median TDF dose of 208 mg/m body surface area (which fell within ±5% of the dose calculated as 8 mg/kg body weight) resulted in lower area under curve (AUC) and the maximum level after the dose was administered, compared to these parameters in adults taking the 300 mg dose. In 40 Thai children ages 3.1–17.7 years (median 12.2) who received TDF at the dose of 7.6 (±1.2) mg/kg or 215 (±26) mg/m, in combination with lamivudine and efavirenz, the 90% confidence interval (CI) for the geometric mean AUC fell within ±20% of that reported in adults and parameters did not differ between those above or below age 12 years. When combined with the results of the previous modeling study which documented higher intracellular TFV-DP concentration in children and adolescents aged between 8.6 and 17 years, drug exposure is expected to be appropriate at the approved dose.
Drug interactions between TDF and protease inhibitors(PIs) have been well documented. In general, TDF decreases drug exposure of atazanavir, while boosted PIs increase drug exposure of TDF. Thus, to reduce the risk of subtherapeutic concentration, atazanavir must always be boosted with ritonavir (atazanavir/r) when used concomitantly with TDF. A study of US children (median age 14 years) demonstrated a trend toward a decrease in TFV renal clearance in children who received TDF with atazanavir/r. However, the 90% CIs of AUC and C24 of TFV overlapped with the target range for all combinations. The recently published population pharmacokinetics data in 93 HIV-infected French children showed that ritonavir-boosted lopinavir (lopinavir/r) decreased TFV clearance by 25%, leading the authors to propose using a lower dose of TDF when coadministered with lopinavir/r (150 mg for 20–40 kg, 225 mg for >40–55 kg and 300 mg for >55 kg body weight). However, that dosing recommendation has not been adopted in the current US or World Health Organization guidelines. In contrast, some studies in youth reported low TFV AUC even when TDF was used with boosted-PI. More research on drug interactions of TDF with boosted PIs is needed to identify the optimal TDF dose in children.
Clinically significant interactions have been reported for TDF with ARVs other than PIs. When coadministered with TDF, didanosine plasma concentration and risk of didanosine toxicities are increased; therefore, TDF and didanosine should generally not be used concomitantly. Based on a pharmacokinetic study showing comparable didanosine AUC among adults who received 250 mg of enteric-coated didanosine tablet in combination with TDF and those who received a standard dose 400 mg didanosine without TDF, the dose of didanosine should be reduced from 400 to 250 mg when coadministered with TDF in adults weighing >60 kg. There is no similar information available in children. Prescription of TDF with didanosine should be avoided.
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