Amprenavir levels boosted tenfold by delavirdine in children

Combining the non-nucleoside reverse transcriptase inhibitor (NNRTI) delavirdine as both an active drug and a booster for the protease inhibitor (PI), amprenavir, in children on salvage therapy appears to be well tolerated and effective after 18 months, according to a small German study published in the July 2nd issue of the journal AIDS.

The study also showed that amprenavir trough levels and total drug exposure declined over 18 months of follow-up, although the patient sample was small.

Previous pharmacokinetic studies in healthy adults have shown that delavirdine is a potent inhibitor of the cytochrome P450 enzyme and increases plasma concentrations of PIs. However, they have also shown that amprenavir is an inducer of delavirdine, resulting in lower delavirdine plasma levels. German doctors, faced with five HIV-infected children with multiple drug failure (including nelfinavir and lopinavir/ritonavir, which were the only two PIs approved for children at the time of the study) in whom genotypic resistance analysis demonstrated susceptibility to amprenavir and all NNRTIs, chose to combine the two drugs in a salvage regimen alongside two additional nucleosides.

Five HIV-infected children, aged 8–14 years old, with a median time of antiretroviral pre-treatment of 37 months (range 34–50 months), having taken a median of four previous NRTIs (range 4–5) and three previous PIs (range 1–4) were given amprenavir, delavirdine and two NRTIs (abacavir with either d4T or 3TC). The doses of amprenavir and delavirdine were set at 40mg/kg body weight per day twice a day and were adjusted for weight gain. At baseline, the median viral load was 5.1 log₁₀ (range 4.3–5.2 log₁₀) and the median absolute CD4 cell count was 699 cells/mm³ (range 666–1878 cells/mm³). Self-reported adherence was good and the only side-effect, which was experienced by three out of the five children, was a mild transient rash for a few days one or two weeks after the start of the treatment.

Pharmacokinetic testing was performed at four weeks, and twelve and 18 months after changing to the new regimen. At four weeks the median amprenavir trough level was 2503ng/ml (range 1931–5194ng/ml). After twelve and 18 months the trough level decreased markedly but stabilised at a median of 595ng/ml (range 464–1777ng/ml). Total exposure (AUC) and trough levels of amprenavir decreased 66% and 78% after twelve months, and 62% and 75% after 18 months, respectively, in comparison with initial values, and stabilised thereafter. In contrast, delavirdine trough levels varied over a wide range during the study period (range 289–5213ng/ml). After twelve months, the mean AUC and trough levels of delavirdine were only 18% and 14% lower, but were approximately 1.5-fold and threefold higher after 18 months. This trend was observed for both drugs in all five children.

The median reduction in viral load was 2.5 log₁₀ (0.6– 2.9 log¹⁰) after three months, 1.6 log₁₀ (0.5–3.4 log₁₀) after twelve months and 1.5 log₁₀ (0.5–3.4 log¹⁰) after 18 months. The median absolute CD4 cell counts were 818 cells/mm³ (548–1471 cells/mm³), 960 cells/mm³ (674–1818 cells/mm³) and 655 cells/mm³ (501–1559 cells/mm³) at three, twelve and 18 months.

This is the first time that this combination has been shown to be safe and effective in HIV-positive children, and, in fact, there has been only one previous case report of using delavirdine and amprenavir in HIV-positive adults – although here they were using delavirdine as a PI booster alongside ritonavir, and not as an active drug.

Although delavirdine is not an approved NNRTI in the EU, is it available on expanded access, and may be a useful alternative to combining PIs with the other NNRTIs, efavirenz and nevirapine, both of which are potent PI inducers. Amprenavir has now been superseded by fosamprenavir, however, and to date there are no interaction studies in adults or children on combining these drugs, and so any combination of delavirdine with either amprenavir or fosamprenavir must be considered experimental.

The authors conclude, “This combination seems to be antiretrovirally effective and safe. Moreover, adherence and tolerance was excellent.” They “observed that delavirdine boosted amprenavir trough levels more than 10-fold above the trough levels observed in amprenavir monotherapy”. Although “plasma levels of delavirdine varied widely [they] were always several fold above susceptible HIV strains, and peak levels were approximately 10% of the maximal measured levels documented in adult studies...It is therefore justified to evaluate the use of delavirdine as a ‘booster drug’ for PI in a greater number of HIV-infected children.”

Further information on this website

Options for children - menu of information

Delavirdine - overview

Boosting alternatives - article in the April 2004 issue of AIDS Treatment Update (pdf)

Europe rejects license for delavirdine, delays on amprenavir - news story