Non-nucleoside reverse transcriptase inhibitors are the smallest class of drugs used for Human Immunodeficiency Virus therapy. The class only contains three medications and all three are indicated for usage against HIV-1. The three medications are delavirdine (Rescriptor), nevirapine (Viramune) and efavirenz (Sustiva). In common ART practice, these drugs are never given alone but rather they are given in combination therapy.
Pharmacia and UpJohn Laboratories manufacture Delavirdine. The recommended dosage is 400mg three times a day and is available in 100mg tablets. Nevirapine is manufactured by a Boehering subsidiary, Roxane Labs, and is recommended at 200mg once daily for 14 days, then increase to 200mg twice daily. Nevirapine is available in 200mg tablets. Efavirenz is recommended at 600mg once daily and is available in 200mg, 100mg and 50mg capsules. It is made by DuPont Pharmaceuticals.
The assay methodology used in achieving PK information about delavirdine was obtained by taking serial plasma and urine collections over a 6 hour period. The samples were then flown to the University at Buffalo, specifically Gene Morse\'s lab, where the pharmacokinetics were determined by high pressure liquid chromatography (1). The pharmacokinetics of nevirapine were determined using HPLC and UV spectroscopy (2). The pharmacokinetics of efavirenz were also determined with plasma samples. The metabolites were obtained using HPLC with UV detection. The subsequent graphs were then compared against previously obtained UV samples of efavirenz (3).
The AUC of efavirenz increased with dose exponentially in monkeys and the average in humans was 57.15mcg/(ml)(hr) (4). In delavirdine, the AUC was seen to increase with dose until a plateau was reached (5). The maximum concentration reached by delavirdine was calculated to be 1 hour after oral administration and reached 29mcg/ml (6, 1). Nevirapine was seen to reach a maximum after 4 hours. The steady state concentration was seen to be 5.5mcg/ml (7). The maximum concentration of efavirenz 4.0mcg/ml was seen 5 hours following dose administration. The steady state concentration of efavirenz was 2.38mcg/ml (8).
The volume of distribution for nevirapine was 1.2-1.4l/kg (7). For some reason the compartmental models for two of the medications were different. Nevirapine fell into a one compartment model, while efavirenz fell into a two compartmental model (7, 9). Efavirenz\' modeling seems to be more realistic and better all around.
The serum half life of delavirdine was 6 hours, nevirapine was 20 hours and efavirenz was 52 hours (6, 7, 6). The total and renal clearances for nevirapine were 3.29L/h and 81.3% was cleared through the urine (7). Efavirenz had a total clearance of 0.186L/hr/kg of which roughly 50% was recovered in the urine (8). It is not known how much of the drug, if any is removed during dialysis.
The bioavailability of nevirapine was seen to be greater than 90% while delavirdine was seen to be 85% bioavailable (7). Efavirenz appears to have a linear relationship between dose and AUC up to a certain point. The graph then levels off, suggesting saturation of metabolism or prolongation of absorption (4). Nevirapine appears to have a linear relationship within the dosage range of 200-400mg (7). Only the IC50 of delavirdine could be uncovered and it was determined to be 0.26uM (1).
The metabolites of each medication included a long list. However, there were no active metabolites for any of the three medications. Nevirapine was metabolized to 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%) and 12-hydroxynevirapine glucuronide (23.7%). 80% of the excreted drug was made up of a glucuronidated compound (7). The major metabolite discovered from delavirdine is desalkyl delavirdine. Most of the Phase I metabolism of delavirdine involves hydroxylation while Phase II metabolism consists of glucuronidation, sulfation and beta-N-acetylglucosamination(10, 11). The major metabolite seen with efavirenz degradation was the O-glucuronide conjugate of the 8-hydroxylated metabolite. Efavirenz was mainly the subject of glucuronidation, much like the other two NNRTIs(3).
Overall, the NNRTIs are a very complex group of medications; despite they\'re only being 3 drugs in the class.