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Antimicrob Agents Chemother. 2005 July; 49(7): 2828–2833.
PMCID: PMC1168662

Safety, Pharmacokinetics, and Efficacy of (+/−)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine with Efavirenz and Stavudine in Antiretroviral-Naïve Human Immunodeficiency Virus-Infected Patients

Abstract

Racivir [RCV; (+/−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine], a 50:50 racemic mixture of the two β nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naïve male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log10 by day 4 and 2.02 to 2.43 log10 by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log10 below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log10 below baseline levels.

Racivir [(+/−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine; (+/−)-FTC; RCV] is a novel drug currently being investigated as a therapeutic agent for human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) infections.

RCV is a 50:50 mixture of the two β enantiomers. The chemical properties of the two enantiomers are essentially identical. As triphosphates, both enantiomers are potent inhibitors of HIV-1 reverse transcriptase (11). Interestingly, studies have shown that they select for different mutations on the HIV-1 reverse transcriptase gene in vitro, M184V for the (−) enantiomer and T215Y for the (+) enantiomer (9, 10). In addition these same studies showed that time to emergence of resistant virus in peripheral blood mononuclear cell culture was prolonged with RCV (14 weeks) compared to either lamivudine (3TC) (9 weeks) or (−)-FTC (9 weeks) (7, 8; R. F. Schinazi, personal communication). This could be advantageous for a therapeutic regimen if the emergence of resistance mutations in patients were also delayed. In vitro studies with HIV have indicated that each enantiomer [(−)-FTC, (+)-FTC] is active against HIV (90% effective concentration [EC90], 0.04 and 0.6 μM, respectively) as well as HBV (EC90, 0.01 and 0.9 μM, respectively) (5, 7). A major advantage of using RCV would be that the virus would be challenged with two different compounds, which should increase the difficulty of developing resistance to both enantiomers (10). Both enantiomers are well absorbed orally and have demonstrated low toxicity in preclinical safety studies (1, 2, 3, 4, 8).

RCV is well tolerated when given orally once a day in rats up to 1 g/kg of body weight per day for 6 months and dogs up to 100 mg/kg per day for 12 months (unpublished data). This is in contrast to other racemic nucleoside mixtures in which toxicity was found to be associated with one of the enantiomers (e.g., BCH-189 and 3TC) (2, 3, 6, 12). Pharmacokinetic studies showed dose-dependent blood plasma levels with mean maximum concentrations (Cmax) of 19 μg/ml in dogs (at 100 mg/kg) and 97 μg/ml in rats (at 1 g/kg). The only adverse event noted in either species was emesis in some dogs at 300 mg/kg/day (unpublished data). At this dose there were no other adverse events or gross toxicity nor abnormal histopathologic findings.

The primary objective of this study was to explore the safety and tolerability of RCV in combination with efavirenz and stavudine (d4T) during a 14-day oral regimen in HIV-infected male subjects. The secondary objectives of this study were to determine the pharmacokinetics of RCV in plasma and urine. Furthermore, a virologic response of HIV to RCV in combination with efavirenz and stavudine was assessed. CD4 cell counts were also measured during the trial.

MATERIALS AND METHODS

The study was approved by the ethics committee of the Berlin (Germany) Chamber of Physicians (Berliner Ärztekammer) and conducted under a U.S. Food and Drug Administration Investigative New Drug Application. Oral and written information was given to all patients, and written consent was obtained before trial-specific procedures.

Protocol outline.

Participants were aged 25 to 45 years and naïve to antiretroviral therapy. Subjects were required to have a viral load above 5,000 copies/ml, a CD4 cell count above 50 cells/μl, and a body mass index above 18 kg/m2. Patients with significantly abnormal laboratory results or electrocardiogram abnormalities or a positive urine drug screening or breath alcohol test were excluded. Further exclusion criteria were participation in another clinical trial within the last 3 months, a history of substance dependency, or any other medical condition compromising adherence to the protocol. It should be noted that none of the subjects enrolled in this study needed to be placed on highly active antiretroviral therapy under current treatment guidelines.

This was a dose escalation study with three groups of six subjects each receiving a 14-day course of 200 mg, 400 mg, or 600 mg of RCV once daily in combination with twice-daily stavudine (30 mg twice a day or 40 mg twice a day for subjects below or above 60 kg of body weight, respectively) and efavirenz (600 mg once daily). Additionally, a control group of six subjects received a 14-day course of 300 mg 3TC once daily, instead of RCV, in combination with stavudine and efavirenz. Since monotherapy with RCV may have placed the subjects at risk of acquiring resistant virus, triple therapy was employed so that multiple-dose pharmacokinetics, safety, and some measure of efficacy could be assessed. The 200-mg-dose group completed the study prior to initiation of the 400-mg-dose group, who completed the study prior to the 600-mg-dose group. For approximately one-half of the subjects, treatment was followed by a 21-day follow-up off therapy. In order to control for adverse events possibly related to concomitant medication, six control subjects were treated with lamivudine, stavudine, and efavirenz.

By protocol all subjects discontinued their RCV-containing triple-drug therapy on day 15. Patients were permitted to start any other antiretroviral therapy thereafter. In some cases, at the discretion of the treating physician, lamivudine was given for 5 days and stavudine was continued for 5 days. This 5-day course of dual therapy was given to prevent the emergence of nonnucleoside reverse transcriptase inhibitor-associated resistance mutations due to the long plasma half-life of efavirenz.

On day 1 (baseline) and day 14 (last day of treatment period) 24-h blood plasma and urine excretion profiles were performed. Intracellular concentrations of the triphosphate form of RCV in peripheral blood mononuclear cells could not be assessed due to technical difficulties such as interference from red blood cells.

RCV and (+)-FTU determination.

A high-performance liquid chromatographic method was developed and validated by Pharmakologische Forschungsgesellschaft Biopharm GmbH, Berlin, Germany. RCV and the deaminated metabolite (+)-FTU [(+)-β-2′,3′-dideoxy-5-fluoro-3′-thiauridine], were extracted from human plasma with perchloric acid, neutralized with KOH, and separated in a Phenomenex Hypersil octadecylsilane (C18) reverse-phase column with a mobile phase of 50 mM phosphate buffer (pH 2.40):methanol:diethylamine (03:7:0,1, vol/vol/vol) with a flow rate of 0.5 ml/min at 35°C. Injections of 50 μl were performed by the autosampler, and a run time of 20 min per injection was used. The pump was programmed to wash the column for approximately 3.0 min by using 25% methanol in water following the elution of the internal standard. The detector was set at a wavelength of 279 nm and an attenuation of 5. Concentrations were determined using standard curves derived from spiked plasma samples.

For RCV and the deaminated metabolite (+)-FTU the following parameters were determined for blood plasma: observed maximum concentration (Cmax), time of observed maximum concentration (tmax), area under the plasma concentration-time curve from time zero until the last quantifiable plasma concentration (AUC0→tlast) (linear trapezoidal rule), area under the plasma concentration-time curve from time zero to infinity (AUC0→∞), apparent terminal rate constant derived from the slope of the log-linear regression of the log-linear terminal portion of the plasma concentration-time curve (λz), and apparent terminal plasma half-life (t1/2 = ln2z). The limit of quantification in plasma was 20 ng/ml (~0.08 μM). The renally excreted amounts of RCV and (+)-FTU were determined from concentrations in urine and urine weights on day 1 and day 14. The following pharmacokinetic parameters were calculated: total amount of drug excreted into urine (Aeur) and renal clearance (CLR). The limit of quantification in urine was 2 μg/ml (~8 μM).

HIV RNA levels.

Throughout the study, serum HIV RNA was measured (Roche Amplicor HIV-1 Monitor test, v1.5-Quantitative). Efficacy was assessed for all subjects using the following values: change from baseline in log10 plasma HIV RNA and AUC of the plasma HIV RNA curve.

CD4 cell counts, electrocardiograms, adverse events, and significant clinical and laboratory findings were collected and documented throughout the trial.

All statistical analyses were done using SAS (version 8.1) software. Pharmacokinetic data were processed with WinNonlin (Windows Non-Linear PK software, version 3.1).

RESULTS

Demographics.

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.

Dosing regimens.

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.

Pharmacokinetics.

The plasma pharmacokinetic profiles for RCV are shown in Fig. Fig.1.1. 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 (Table11).

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 ...
TABLE 1.
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 (Table2).2). 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.

TABLE 2.
Pharmacokinetic parameters for (+)-FTU (mean ± standard deviation) in blood plasma

Approximately 40 to 45% of the drug was excreted as unchanged RCV (RCV) (Table (Table3),3), and 27 to 40% was excreted as its metabolite (+)-FTU (Table (Table4)4) 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.

TABLE 3.
Excretion of unchanged RCV into urine
TABLE 4.
Excretion of the metabolite (+)-FTU into urine after administration of RCV

Safety.

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.

Virologic response was estimated as the change of plasma HIV RNA copies/ml. All tested treatment combinations and doses were effective (Fig. (Fig.1).1). 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 (Table5).5). 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.

TABLE 5.
HIV RNA levels in individual subjects during and after treatment

DISCUSSION

This phase Ib/IIa study demonstrated a profile of RCV as safe and well tolerated when taken over 14 days. The doses chosen for this study were based on the “no adverse effect dose level” in dogs, i.e., 100 mg/kg for 12 months. In this trial, weight-related doses ranged from approximately 3 mg/kg (200 mg of RCV) to 8 mg/kg (600 mg of RCV). Based on previous studies we expected a clinically effective and safe dose of RCV to be between 200 mg and 600 mg once daily. With the possible exception of headaches the tolerability of RCV seemed to be comparable with those of lamivudine and emtricitabine. With respect to the possible flare-up of chronic hepatitis B in a subject receiving 400 mg RCV, further investigations are required for this coinfected group of patients. It was noted that plasma HBV DNA levels, in this subject, dropped approximately 2 log10 over the 14-day treatment period. Unfortunately no samples were available to determine HBV DNA levels during the follow-up period. The other HBV-coinfected subject who was in the 3TC group showed no evidence of a flare-up, most probably due to the fact that 3TC dosing was not stopped after 14 days. The change in HBV viral load in this subject was not measured due to the unavailability of samples for testing.

Maximum plasma concentrations of both RCV and its metabolite (+)-FTU were reached rapidly and were proportional to the administered dose. The areas under the plasma concentration curve for both compounds were directly related to dosage of RCV, indicating linear pharmacokinetics.

Most of the total dose (70% to 80%) was excreted into urine over 24 h, 40 to 45% as unchanged RCV and 27 to 40% as (+)-FTU. The plasma half-life of RCV was several hours, thus encouraging further trials assessing the once-daily regimen. The percentage of dose metabolized to (+)-FTU actually decreased as the dose of RCV was increased, suggesting that metabolism may be saturable.

Virologic response was good in all groups (Fig. (Fig.2).2). Viral suppression was not dose dependent, indicating that the lowest dose of RCV (200 mg twice daily) was safe with regards to the potential for emergence of resistance. These results are not unexpected given the fact that each group received three potent antiretroviral drugs and that the mean plasma concentration of RCV at 24 h (approximately 0.1 μM) remained at or above the in vitro EC90 (0.04 to 0.1 μM). However, this issue will be addressed in long-term safety and efficacy studies. Viral suppression was maintained up to 2 weeks after cessation of therapy with these combinations of antiretroviral drugs most probably due to the long plasma half-life of efavirenz. Based on all these data a once-daily regimen with RCV will be investigated further.

FIG. 2.
Change in plasma HIV RNA in all subjects. Subjects received stavudine and efavirenz in combination with 200 mg ([filled lozenge]), 400 mg ([filled square]), or 600 mg ([filled triangle]) RCV once a day or 150 mg lamivudine (×) twice a day for 14 days. There were six ...

In conclusion, RCV is a safe and novel nucleoside reverse transcriptase inhibitor with promising antiviral features for the treatment of HIV-1. Phase II and III trials are currently planned in treatment-naïve and experienced patients.

Acknowledgments

Raymond F. Schinazi is a founder, director, and consultant of Pharmasset and as such holds equity interest in the company. His particulars have been reviewed by Emory University's Conflict of Interest Committee. The Schinazi laboratory received no funding from Pharmasset. Robert Murphy is a consultant to Pharmasset and assisted in the design of the study including review of safety and efficacy data.

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