TENOFOVIR DISOPROXIL FUMARATE (Page 7 of 10)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate 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.
Tenofovir disoproxil fumarate 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, tenofovir disoproxil fumarate was negative when administered to male mice.
Impairment of Fertility
There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate 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 seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
13.2 Animal Toxicology and/or Pharmacology
Tenofovir and tenofovir disoproxil fumarate 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 4 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) 2-20 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 tenofovir disoproxil fumarate in adults and pediatric subjects were evaluated in the trials summarized in Table 19.
Table 19 Trials Conducted with Tenofovir Disoproxil Fumarate in Adults and Pediatric Subjects for HIV-1 Treatment and Chronic HBV Treatment
| a. Randomized and dosed. | |||
| b. Randomized, double-blind, active-controlled trial. | |||
| c. Randomized, open-label active-controlled trial. | |||
| d. Randomized, double-blind, placebo-controlled trial. | |||
| Trial | Population | Study Arms (N)a | Timepoint (Week) |
| Trial 903b (NCT00158821) | HIV-1 treatment-naïve adults | tenofovir disoproxil fumarate +lamivudine+efavirenz (299) stavudine+lamivudine+efavirenz (301) | 144 |
| Trial 934c (NCT00112047) | emtricitabine+ tenofovir disoproxil fumarate +efavirenz (257) zidovudine/lamivudine+efavirenz (254) | 144 | |
| Trial 907d (NCT00002450) | HIV-1 treatment-experienced adults | tenofovir disoproxil fumarate (368) Placebo (182) | 24 |
| Trial 0102b (NCT00117676) | HBeAg-negative adults with chronic HBV | tenofovir disoproxil fumarate (250) HEPSERA (125) | 48 |
| Trial 0103b (NCT00116805) | HBeAg-positive adults with chronic HBV | tenofovir disoproxil fumarate (176) HEPSERA (90) | 48 |
| Trial 121b (NCT00737568) | Adults with lamivudine-resistant chronic HBV | tenofovir disoproxil fumarate (141) | 96 |
| Trial 0108b (NCT00298363) | Adults with chronic HBV and decompensated liver disease | tenofovir disoproxil fumarate (45) | 48 |
| Trial 352c (NCT00528957) | HIV-1 treatment experienced pediatric subjects 2 years to <12 years | tenofovir disoproxil fumarate (44) stavudine or zidovudine (48) | 48 |
| Trial 321d (NCT00352053) | HIV-1 treatment-experienced pediatric subjects 12 years to <18 years | tenofovir disoproxil fumarate (45) Placebo (42) | 48 |
| Trial 115d (NCT00734162) | Pediatric subjects 12 years to <18 years with chronic HBV | tenofovir disoproxil fumarate (52) Placebo (54) | 72 |
Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
14.2 Clinical Trial Results in Adults with HIV-1 Infection
Treatment-Naïve Subjects: Trial 903
Data through 144 weeks are reported for Trial 903, a double-blind, active-controlled multicenter trial comparing tenofovir disoproxil fumarate (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18-64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm 3 (range 3-956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417-5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm 3. Table 20 provides treatment outcomes through 48 and 144 weeks.
Table 20 Outcomes of Randomized Treatment at Week 48 and 144 (Trial 903)
| a. Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144. | ||||
| b. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144. | ||||
| c. Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons. | ||||
| Outcomes | At Week 48 | At Week 144 | ||
| Tenofovir disoproxil fumarate + 3TC + EFV (N=299) | d4T + 3TC + EFV (N=301) | Tenofovir disoproxil fumarate + 3TC + EFV (N=299) | d4T + 3TC + EFV (N=301) | |
| Responder a | 79% | 82% | 68% | 62% |
| Virologic failure b | 6% | 4% | 10% | 8% |
| Rebound | 5% | 3% | 8% | 7% |
| Never suppressed | 0% | 1% | 0% | 0% |
| Added an antiretroviral agent | 1% | 1% | 2% | 1% |
| Death | <1% | 1% | <1% | 2% |
| Discontinued due to adverse event | 6% | 6% | 8% | 13% |
| Discontinued for other reasons c | 8% | 7% | 14% | 15% |
Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4 + cell count (< or ≥200 cells/mm 3). Through 144 weeks of therapy, 62% and 58% of subjects in the tenofovir disoproxil fumarate and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 + cell count was 263 cells/mm 3 for the tenofovir disoproxil fumarate arm and 283 cells/mm 3 for the stavudine arm.
Through 144 weeks, 11 subjects in the tenofovir disoproxil fumarate group and 9 subjects in the d4T group experienced a new CDC Class C event.
Treatment-Naïve Subjects: Trial 934
Data through 144 weeks are reported for Trial 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + tenofovir disoproxil fumarate administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir with efavirenz in place of emtricitabine + tenofovir disoproxil fumarate with efavirenz. Subjects had a mean age of 38 years (range 18-80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm 3 (range 2-1191) and median baseline plasma HIV-1 RNA was 5.01 log 10 copies/mL (range 3.56-6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm 3); 41% had CD4+ cell counts <200 cells/mm 3 and 51% of subjects had baseline viral loads >100,000 copies/mL.Table 21 provides treatment outcomes through 48 and144 weeks for those subjects who did not have EFV resistance at baseline.
Table 21 Outcomes of Randomized Treatment at Week 48 and 144 (Trial 934)
| a. Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the 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 +Tenofovir disoproxil fumarate + EFV (N=244) | AZT/3TC+EFV (N=243) | FTC +Tenofovir disoproxil fumarate + EFV (N=227) a | AZT/3TC+EFV (N=229) a | |
| Responder b | 84% | 73% | 71% | 58% |
| Virologic failure c | 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 reasons d | 10% | 14% | 20% | 22% |
Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir disoproxil fumarate group and the zidovudine/lamivudine 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 largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir disoproxil fumarate group and the zidovudine/lamivudine 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/mm 3 in the emtricitabine+ tenofovir disoproxil fumarate group and 158 cells/mm 3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm 3 at Week 144).
Through 48 weeks, 7 subjects in the emtricitabine + tenofovir disoproxil fumarate group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Treatment-Experienced Subjects: Trial 907
Trial 907 was a 24-week, double-blind, placebo-controlled multicenter trial of tenofovir disoproxil fumarate added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label tenofovir disoproxil fumarate for an additional 24 weeks. Subjects had a mean baseline CD4 + cell count of 427 cells/mm 3 (range 23-1385), median baseline plasma HIV-1 RNA of 2340 (range 50-75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.
Table 22 provides the percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks.
Table 22 Outcomes of Randomized Treatment (Trial 907)
| a. Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively. | ||||
| b. Subjects with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively. | ||||
| c. Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons. | ||||
| Outcomes | 0-24 weeks | 0-48 weeks | 24-48 weeks | |
| Tenofovir disoproxil fumarate (N=368) | Placebo (N=182) | Tenofovir disoproxil fumarate (N=368) | Placebo Crossover to tenofovir disoproxil fumarate (N=170) | |
| HIV-1 RNA <400 copies/mL a | 40% | 11% | 28% | 30% |
| Virologic failure b | 53% | 84% | 61% | 64% |
| Discontinued due to adverse event | 3% | 3% | 5% | 5% |
| Discontinued for other reasons c | 3% | 3% | 5% | 1% |
At 24 weeks of therapy, there was a higher proportion of subjects in the tenofovir disoproxil fumarate arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm 3 for the tenofovir disoproxil fumarate group and -5 cells/mm 3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm 3 for the tenofovir disoproxil fumarate group.
Through Week 24, one subject in the tenofovir disoproxil fumarate group and no subjects in the placebo arm experienced a new CDC Class C event.
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