Emtricitabine and Tenofovir Disoproxil Fumarate (Page 8 of 10)

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Emtricitabine: In long-term oral carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose).

FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.

FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

TDF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.

There were no effects on fertility, mating performance, or early embryonic development when TDF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in four animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2 to 20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14. CLINICAL STUDIES

14.1 Overview of Clinical Trials

The efficacy and safety of emtricitabine and tenofovir disoproxil fumarate have been evaluated in the studies summarized in Table 13.

Table 13 Trials Conducted with Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 Treatment and HIV-1 PrEP

a Randomized and dosed.

b Randomized, open label, active-controlled trial.

c Randomized, double-blind, placebo-controlled trial.

Trial Population Study Arms (N)a Timepoint
Study 934b (NCT00112047) HIV-infected, treatment-naïve adults FTC+TDF + efavirenz (257) zidovudine/lamivudine + efavirenz (254) 48 Weeks
iPrExc (NCT00458393) HIV-seronegative men or transgender women who have sex with men emtricitabine and tenofovir disoproxil fumarate (1,251) Placebo (1,248) 4,237 person-years
Partners PrEPc (NCT00557245) HIV serodiscordant heterosexual couples emtricitabine and tenofovir disoproxil fumarate (1,583) Placebo (1,586) 7,827 person-years

14.2 Clinical Trial Results for Treatment of HIV-1: Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing FTC+TDF administered in combination with efavirenz (EFV) versus zidovudine (AZT)/lamivudine (3TC) fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve adult subjects. From Weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate with EFV in place of FTC+TDF with EFV. Subjects had a mean age of 38 years (range 18 to 80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2 to 1,191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56 to 6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥ 200 cells/mm3); 41% had CD4+ cell counts < 200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline are presented in Table 14.

Table 14 Virologic Outcomes of Randomized Treatment at Weeks 48 and 144 (Study 934)

a Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA < 400 copies/mL) but did not consent to continue trial after Week 48 or Week 96 were excluded from analysis.

b Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Weeks 48 and 144.

c Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Weeks 48 and 144.

d Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation, and other reasons.

Outcomes At Week 48 At Week 144
FTC+TDF +EFV (N=244) AZT/3TC +EFV (N=243) FTC+TDF +EFV (N=227)a AZT/3TC +EFV (N=229) a
Responderb 84% 73% 71% 58%
Virologic failurec 2% 4% 3% 6%
Rebound 1% 3% 2% 5%
Never suppressed 0% 0% 0% 0%
Change in antiretroviral regimen 1% 1% 1% 1%
Death < 1% 1% 1% 1%
Discontinued due to adverse event 4% 9% 5% 12%
Discontinued for other reasonsd 10% 14% 20% 22%

Through Week 48, 84% and 73% of subjects in the FTC+TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA < 400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA < 400 copies/mL through 48 weeks is largely due to the higher number of discontinuations due to adverse events and other reasons in the AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the FTC+TDF group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the FTC+TDF group and 158 cells/mm3 in the AZT/3TC group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the FTC+TDF group and 5 subjects in the AZT/3TC group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

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