Twenty-five subjects were enrolled in this study. One subject dropped out on day 4 due to adverse events possibly related to efavirenz and/or RCV. The mean age was 33.2 years (standard deviation, ±5.8; range, 25 to 47), mean body weight was 72.1 kg (±9.6; range, 52.0 to 93.2), and mean body mass index was 22.5 kg/m2 (±2.4; range, 18.5 to 28.4). Two subjects were suffering from chronic hepatitis B. No relevant coexisting diseases were found at screening, and no interacting drugs were taken.
No changes in CD4 cell counts were observed during the trial. Mean baseline values were 662 ± 257 cells/μl, 487 ± 222 cells/μl, 431 ± 295 cells/μl, and 545 ± 432 cells/μl in patients receiving 200 mg, 400 mg, or 600 mg of RCV or receiving lamivudine, respectively.
Subjects received stavudine and efavirenz in combination with 200 mg, 400 mg, or 600 mg RCV once a day or 150 mg lamivudine twice a day for 14 days. Per the protocol, from day 15 onward subjects were permitted to switch their antiretroviral drugs or, in the case of the lamivudine group, to continue their regimen. There were six subjects in each dosing group with five/six subjects in the 200- and 400-mg groups stopping all antiretroviral drugs after day 14. At the end of the 14-day treatment phase five/six subjects in the 600-mg-RCV group and five/six subjects in the lamivudine group received stavudine plus lamivudine for an additional 5 days (days 15 to 19) and then stopped all antiretroviral drugs. One subject in each group was switched to lamivudine plus stavudine plus efavirenz on day 15 and remained on this regimen during the follow-up period.
The plasma pharmacokinetic profiles for RCV are shown in Fig. . Mean peak plasma concentration (Cmax) values for RCV were 1,336 ± 520 ng/ml, 2,597 ± 482 ng/ml, and 4,140 ± 1,404 ng/ml for the groups taking 200 mg, 400 mg, and 600 mg of RCV on day 1, respectively. Cmax values on day 14 were similar. A dose-dependent relationship between mean peak plasma concentrations of RCV was found for the three treatment groups on days 1 and 14 (Table ).
FIG. 1. Mean plasma concentrations of RCV following once-daily dosing. Values following the first dose of RCV on day 1 and the 14th dose on day 14 were determined by high-performance liquid chromatography as described in Materials and Methods. Oral doses of 200 (more ...)
Pharmacokinetic parameters for RCV (mean ± standard deviation) in blood plasma
RCV reached its maximum plasma concentration in less than 1 h. Mean tmax of RCV ranged from 0.7 to 0.92 h on day 1 and from 0.60 to 0.67 h on day 14 and was not related to the dose administered.
Mean area under the curve (AUC0→tlast) and extrapolated AUC0→∞ were similar on day 1 and day 14 in each group. A relationship between dose and these parameters was apparent; however, this relationship was not strictly dose proportional.
t1/2 was approximately 6 h for the treatment doses 200 mg and 400 mg on day 1 as well as on day 14. t1/2 for the 600-mg group was shorter—approximately 3 h on day 1 and day 14.
Mean plasma Cmax of the metabolite (+)-FTU ranged from 1,335 to 2,860 ng/ml on day 1 and from 1,946 to 2,776 ng/ml on day 14. (+)-FTU levels were directly related to the RCV dosage administered.
(+)-FTU reached its maximum concentration in plasma in less than 1 h on day 1 and day 14 (Table ). Mean tmax of (+)-FTU ranged from 0.58 to 0.8 h for all doses of RCV, suggesting a fast metabolism of RCV. Mean AUC0→tlast and extrapolated AUC0→∞ of (+)-FTU showed a similar relationship to dosage as that of RCV. The half-life of (+)-FTU (t1/2) ranged from 3 to 4 h for all treatment doses. No differences were found between day 1 and day 14.
Pharmacokinetic parameters for (+)-FTU (mean ± standard deviation) in blood plasma
Approximately 40 to 45% of the drug was excreted as unchanged RCV (RCV) (Table ), and 27 to 40% was excreted as its metabolite (+)-FTU (Table ) in all groups. It is of interest that the percentage of the total dose recovered as the metabolite actually decreased with the highest dose. Renal clearance ranged from 295 to 457 ml/min, indicating that the drug was eliminated by glomerular filtration and active tubular secretion. Nearly the full amount of RCV was excreted renally within a day.
Excretion of unchanged RCV into urine
Excretion of the metabolite (+)-FTU into urine after administration of RCV
The AIDS Clinical Trial Group (ACTG) classification for adverse events was used in this study. RCV was well tolerated with no significant clinical or laboratory adverse events. The adverse events reported most often during the 14-day treatment period were dizziness (six, seven, nine, and five episodes in subjects receiving 200 mg, 400 mg, and 600 mg of RCV or receiving lamivudine, respectively) and headache (five, two, five, and one episode, respectively). Both were mild to moderate in intensity and possibly related to study medication in 85% (dizziness) and 68% (headache). Other adverse events reported on more than three occasions during the trial were impaired concentration, nausea, fatigue, common cold, and ocular discomfort. One subject taking 600 mg of RCV reported “heartburn” that was possibly related to the trial drug. It should be noted that the headaches were associated primarily with common colds that occurred during the autumn when this study was being conducted. This may account for the apparently higher level of headaches in the RCV groups.
One subject taking 600 mg of RCV withdrew his consent on day 4 due to moderate nausea and vomiting associated with mild dizziness possibly caused by RCV or efavirenz.
No relevant electrocardiographic, biochemical, or hematological changes were found. One subject, who had chronic hepatitis B and was taking 400 mg of RCV, had high levels of liver enzymes aspartate aminotransferase and alanine aminotransferase during the whole study (ACTG grade ≤1). These values did not decrease during the course of the study. He showed a significant elevation (ACTG grade 1) of liver transaminases due to a flare-up of his chronic hepatitis B infection after cessation of therapy, and these values were reported by the physician as an adverse event of elevated liver enzymes severe in intensity on day 28, which was considered to be possibly related to study drug (82.6-U/liter aspartate aminotransferase; normal range, 17 to 59 U/liter; 119.6-U/liter alanine aminotransferase; normal range, 21 to 72 U/liter). Other laboratory parameters did not show values of clinical significance.
Another subject taking 200 mg of RCV presented with significantly elevated creatinine phosphokinase after physical exercise. There were no serious adverse events as defined by the ACTG classification during the trial or follow-up period.
Virologic response was estimated as the change of plasma HIV RNA copies/ml. All tested treatment combinations and doses were effective (Fig. ). On day 14, mean decreases in plasma HIV RNA were 1.92 log10, 2.03 log10, 2.17 log10, and 2.25 log10 for the groups treated with 200 mg, 400 mg, and 600 mg RCV and with lamivudine, respectively. The effect was not related to the RCV dose. The mean reduction in plasma HIV RNA on day 28, 14 days after cessation of RCV, compared to baseline was 2.15 log10, 2.18 log10, 2.06 log10, and 2.19 log10 for the groups as listed above. It is important to note that in the 200- and 400-mg-RCV groups the HIV RNA levels remained suppressed in those subjects who received no antiretroviral drugs from day 15 to day 35 (Table ). The mean HIV RNA levels on day 35 for these subjects were still 1.57 log10 and 1.26 log10 below baseline for the 200- and 400-mg groups, respectively.
HIV RNA levels in individual subjects during and after treatment