Tenofovir in HIV-Infected Children
Tenofovir in HIV-Infected Children
Are there any specific considerations or recommendations one should be aware of when using tenofovir in children or infants?
Tenofovir disoproxil fumarate (tenofovir DF; Viread) is the prodrug for tenofovir, the first nucleotide analogue drug approved by the US Food and Drug Administration. Although it is not approved for children, it has shown promise both for the pediatric population and for use in the prevention of maternal-to-child transmission (MTCT) of HIV. Studies in the animal model have shown excellent results in preventing MTCT. Although this drug is well studied in adults, there is very limited information on its use in children.
Tenofovir DF is a nucleotide analog of adenine 5' monophosphate and a reverse transcriptase inhibitor that has excellent oral bioavailability. It is converted to tenofovir in serum and tissues by esterases and is phosphorylated intracellularly to a diphosphate form. Tenofovir diphosphate is a chain terminator and has reverse transcriptase properties. Its unique characteristics make it useful in combination antiretroviral regimens.
The pharmacologic properties of tenofovir are well described in adults, but only recently have data been published regarding the pharmacologic properties of this agent in children. Tenofovir has a long intracellular half-life and serum half-life of 14 hours. The usual adult dose is 300 mg, with drug levels increasing over the first 3 hours following dosing. (Coadministration with a fatty meal or lopinavir/ritonavir increases drug levels by an additional 40% and 34%, respectively.) The drug is eliminated in the urine unchanged. Thus, this once-daily dosing makes it an attractive drug for use in children and infants as well. At present, there is no available liquid formulation, however, and this limits its utility.
The recent study by Hazra and colleagues included 18 children 4-18 years of age who were able to swallow tablets. As in adults, after oral administration, the drug was rapidly absorbed with a Tmax of 1.3 hours. Results from the study indicated that following a single dose of 175 mg/m, which is comparable to the adult 300-mg dose, the AUC and Cmax were 34% and 27%, respectively, lower than levels observed in adults. However, the steady-state levels were comparable to those observed in adults. The explanation for the lower levels after a single dose was uncertain but suggests poorer bioavailability or increased renal clearance. However, when combined with other antiretrovirals, the steady-state levels seemed adequate, which suggests that a pediatric dosage similar to the adult dosage may be used. Food also appeared to increase bioavailability, as in adults.
Clinicians continue to search for regimens that are simple but have little toxicity for their patients. For this reason regimens that include 3 nucleosides have become popular. Since each component may be given once a day, a combination of tenofovir + lamivudine + didanosine has been tested but results have been disappointing in adults. However, combining tenofovir with protease inhibitors has resulted in significant viral load reductions in highly experienced patients (-0.5 to -0.6 log10).
Because of studies done in infant monkeys that have shown stunted growth and bone toxicity, there has been significant concern as to the use of this drug in children and pregnant women. Although there are no clinical studies in children, these findings warrant close monitoring for bone and joint abnormalities. Renal toxicities, which were of major concern with adefovir, have to date been noted infrequently among adults. As with nucleoside analogs, mitochondrial toxicity may be expected, but again, there is no information in this regard in children. Regarding drug interactions, there is concern that use with didanosine might result in increased didanosine levels and result in toxicities, such as nephropathy or pancreatitis.
One advantage of tenofovir is the resistance profile. Studies from adults suggest that even among highly experienced patients tenofovir may be efficacious. The important K65R mutation, which causes reduced susceptibility to didanosine and abacavir, develops slowly and in one study was only seen in a small percentage of patients.
In conclusion, although tenofovir is not approved in children, recent studies suggest a pharmacokinetic profile similar to adults. However, no information is available as to short- and long-term toxicities, although it may be expected that the toxicity profile would be similar to that of adults. Information related to bone and joint formation will be needed before recommendations can be made regarding the long-term use of this drug.
Are there any specific considerations or recommendations one should be aware of when using tenofovir in children or infants?
Tenofovir disoproxil fumarate (tenofovir DF; Viread) is the prodrug for tenofovir, the first nucleotide analogue drug approved by the US Food and Drug Administration. Although it is not approved for children, it has shown promise both for the pediatric population and for use in the prevention of maternal-to-child transmission (MTCT) of HIV. Studies in the animal model have shown excellent results in preventing MTCT. Although this drug is well studied in adults, there is very limited information on its use in children.
Tenofovir DF is a nucleotide analog of adenine 5' monophosphate and a reverse transcriptase inhibitor that has excellent oral bioavailability. It is converted to tenofovir in serum and tissues by esterases and is phosphorylated intracellularly to a diphosphate form. Tenofovir diphosphate is a chain terminator and has reverse transcriptase properties. Its unique characteristics make it useful in combination antiretroviral regimens.
The pharmacologic properties of tenofovir are well described in adults, but only recently have data been published regarding the pharmacologic properties of this agent in children. Tenofovir has a long intracellular half-life and serum half-life of 14 hours. The usual adult dose is 300 mg, with drug levels increasing over the first 3 hours following dosing. (Coadministration with a fatty meal or lopinavir/ritonavir increases drug levels by an additional 40% and 34%, respectively.) The drug is eliminated in the urine unchanged. Thus, this once-daily dosing makes it an attractive drug for use in children and infants as well. At present, there is no available liquid formulation, however, and this limits its utility.
The recent study by Hazra and colleagues included 18 children 4-18 years of age who were able to swallow tablets. As in adults, after oral administration, the drug was rapidly absorbed with a Tmax of 1.3 hours. Results from the study indicated that following a single dose of 175 mg/m, which is comparable to the adult 300-mg dose, the AUC and Cmax were 34% and 27%, respectively, lower than levels observed in adults. However, the steady-state levels were comparable to those observed in adults. The explanation for the lower levels after a single dose was uncertain but suggests poorer bioavailability or increased renal clearance. However, when combined with other antiretrovirals, the steady-state levels seemed adequate, which suggests that a pediatric dosage similar to the adult dosage may be used. Food also appeared to increase bioavailability, as in adults.
Clinicians continue to search for regimens that are simple but have little toxicity for their patients. For this reason regimens that include 3 nucleosides have become popular. Since each component may be given once a day, a combination of tenofovir + lamivudine + didanosine has been tested but results have been disappointing in adults. However, combining tenofovir with protease inhibitors has resulted in significant viral load reductions in highly experienced patients (-0.5 to -0.6 log10).
Because of studies done in infant monkeys that have shown stunted growth and bone toxicity, there has been significant concern as to the use of this drug in children and pregnant women. Although there are no clinical studies in children, these findings warrant close monitoring for bone and joint abnormalities. Renal toxicities, which were of major concern with adefovir, have to date been noted infrequently among adults. As with nucleoside analogs, mitochondrial toxicity may be expected, but again, there is no information in this regard in children. Regarding drug interactions, there is concern that use with didanosine might result in increased didanosine levels and result in toxicities, such as nephropathy or pancreatitis.
One advantage of tenofovir is the resistance profile. Studies from adults suggest that even among highly experienced patients tenofovir may be efficacious. The important K65R mutation, which causes reduced susceptibility to didanosine and abacavir, develops slowly and in one study was only seen in a small percentage of patients.
In conclusion, although tenofovir is not approved in children, recent studies suggest a pharmacokinetic profile similar to adults. However, no information is available as to short- and long-term toxicities, although it may be expected that the toxicity profile would be similar to that of adults. Information related to bone and joint formation will be needed before recommendations can be made regarding the long-term use of this drug.
Source...