Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Darunavir (TMC114) is a newly developed HIV-1 protease inhibitor with potent antiviral activity against both wild-type and multidrug resistant HIV-1 strains. The drug is currently approved by the US FDA for antiretroviral treatment-experienced patients with limited therapeutic options. The approved dosage of darunavir is 600 mg in combination with ritonavir 100mg twice daily. Darunavir is rapidly absorbed after oral administration, reaching peak plasma concentrations after 2.5-4 hours. Absorption is followed by a fast distribution/elimination phase and a subsequent slower elimination phase with a terminal elimination half-life of 15 hours in the presence of low-dose ritonavir. Darunavir is approximately 95% plasma protein bound, mainly to alpha(1)-acid glycoprotein. Systemic exposure is increased by 30% when darunavir is taken with a meal. Darunavir is extensively and almost exclusively metabolised by cytochrome P450 (CYP) 3A4. Coadministration with small doses of the strong CYP3A4 inhibitor ritonavir results in an increase in darunavir bioavailability from 37% to 82%. Darunavir and its metabolites are mainly excreted in faeces (79.5%) and, to a lesser extent, in urine (13.9%). With regard to the necessary coadministration with low-dose ritonavir as a potent CYP3A4 inhibitor, coadministration of other substrates of CYP3A4 with darunavir/ritonavir requires caution or is even contraindicated. Guidance is derived from drug-drug interaction trials and experience from comparable ritonavir-boosted protease inhibitor regimens.
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PMID:Clinical pharmacokinetics of darunavir. 1771 72

A dog model was developed to test the capacity of boosters for antiretroviral medication. Two dogs were implanted with a modified constant-flow Codman 3000 infusion pump, adapted to release viscous solutions of darunavir (TMC114) at a constant rate of 25mg/dog/day in the venous blood stream. Booster candidates were given by oral gavage for at least 4 days up to maximum 7 days in cross-over fashion, separated by a wash-out period of minimum 1 week. The booster candidates were tested at doses of 20 and/or 40mg/kg/day: blood sampling for determination of the boosting effect was performed on the last day of booster administration. The model allowed to (1) compare the boosting ratio of these booster candidates based on the exposure (determination of the area under the curve (AUC) of darunavir in presence versus absence of the booster candidate), (2) detect delay in boosting activity by evaluation of the shift of Cmax of darunavir following booster administration versus the Cmax of the booster candidate) and (3) calculate the intrinsic booster capacity, by correcting for the systemic exposure of booster candidate by normalizing the booster ratio for the booster's AUC. The latter parameter (intrinsic booster capacity) allows to determine the booster's metabolic contribution in inhibiting the metabolism of antiretroviral medication (most likely via inhibition of CYP3A4), minimizing the impact of potential effects of the booster at the level of the gastro-intestinal tract.
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PMID:Dog model with implanted pump to test boosters for antiretroviral medication. 1808 80