Abacavir Sulfate (Page 7 of 9)

Resistance

HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture and were also obtained from subjects treated with abacavir. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I in RT contributed to abacavir resistance. In a trial of therapy-naive adults receiving abacavir 600 mg once daily (n = 384) or 300 mg twice daily (n = 386), in a background regimen of lamivudine 300 mg once daily and efavirenz 600 mg once daily (CNA30021), the incidence of virologic failure at 48 weeks was similar between the two groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this trial showed that the RT substitutions that emerged during abacavir once daily and twice daily therapy were K65R, L74V, Y115F, and M184V/I. The substitution M184V/I was the most commonly observed substitution in virologic failure isolates from subjects receiving abacavir once daily (56%, 10/18) and twice daily (40%, 8/20).

Thirty-nine percent (7/18) of the isolates from subjects who experienced virologic failure in the abacavir once daily arm had a greater than 2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).

Cross-resistance

Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in cell culture and in subjects. The K65R substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V substitution can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. An increasing number of thymidine analogue mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity:

Abacavir was administered orally at three dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose. It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Mutagenicity:

Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay.

Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

Impairment of Fertility:

Abacavir had no adverse effects on the mating performance or fertility of male and female rats at a dose approximately 8 times the human exposure at the recommended dose based on body surface area comparisons.

13.2 Animal Toxicology and/or Pharmacology

Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.

14 CLINICAL STUDIES

14.1 Adults

Therapy-naive Adults

CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either abacavir (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), Caucasian (51%), black (21%), and Hispanic (26%). The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells/mm3 , and median plasma HIV-1 RNA was 4.79 log10 copies/mL. The outcomes of randomized treatment are provided in Table 7.

Table 7. Outcomes of Randomized Treatment Through Week 48 (CNA30024)
*
Subjects achieved and maintained confirmed HIV-1 RNA ≤ 50 copies/mL (< 400 copies/mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR®** standard test 1.0 PCR).
Includes viral rebound, insufficient viral response according to the investigator, and failure to achieve confirmed ≤ 50 copies/mL by Week 48.
Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.
Outcome Abacavir plusLamivudine plus Efavirenz(n = 324) Zidovudine plus Lamivudineplus Efavirenz(n = 325)
Responder * 69% (73%) 69% (71%)
Virologic failures 6% 4%
Discontinued due to adverse reactions 14% 16%
Discontinued due to other reasons 10% 11%

After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells/mm3 in the group receiving abacavir and 155 cells/mm3 in the zidovudine group. Through Week 48, eight subjects (2%) in the group receiving abacavir (five CDC classification C events and three deaths) and five subjects (2%) on the zidovudine arm (three CDC classification C events and two deaths) experienced clinical disease progression.

CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either abacavir (300 mg twice daily) plus COMBIVIR®** (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR®** twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies/mL and plasma HIV-1 RNA greater than 100,000 copies/mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells/mm3 , and median baseline plasma HIV-1 RNA was 4.8 log10 copies/mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies/mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.

Table 8. Outcomes of Randomized Treatment Through Week 48 (CNA3005)
*
Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL.
Includes viral rebound and failure to achieve confirmed < 400 copies/mL by Week 48.
Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.
Outcome Abacavir plusLamivudine/Zidovudine(n = 262) Indinavir plusLamivudine/Zidovudine(n = 265)
Responder * 49% 50%
Virologic failures 31% 28%
Discontinued due to adverse reactions 10% 12%
Discontinued due to other reasons 11% 10%

Treatment response by plasma HIV-1 RNA strata is shown in Table 9.

Table 9. Proportions of Responders Through Week 48 By Screening Plasma HIV-1 RNA Levels (CNA3005)
Screening HIV-1 RNA(copies/mL) Abacavir plusLamivudine/Zidovudine(n = 262) Indinavir plusLamivudine/Zidovudine(n = 265)
< 400 copies/mL n < 400 copies/mL n
≥ 10,000 to ≤ 100,000 50% 166 48% 165
> 100,000 48% 96 52% 100

In subjects with baseline viral load greater than 100,000 copies/mL, percentages of subjects with HIV-1 RNA levels less than 50 copies/mL were 31% in the group receiving abacavir versus 45% in the group receiving indinavir.

Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells/mm3 was observed in both treatment arms. Through Week 48, nine subjects (3.4%) in the group receiving abacavir (six CDC classification C events and three deaths) and three subjects (1.5%) in the group receiving indinavir (two CDC classification C events and one death) experienced clinical disease progression.

CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells/mm3 (range: 21 to 918 cells/mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies/mL (range: 2.6 to 6.99 log10 copies/mL).

The outcomes of randomized treatment are provided in Table 10.

Table 10. Outcomes of Randomized Treatment Through Week 48 (CNA30021)
*
Subjects achieved and maintained confirmed HIV-1 RNA < 50 copies/mL (<400 copies/mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).
Includes viral rebound, failure to achieve confirmed < 50 copies/mL (< 400 copies/mL) by Week 48, and insufficient viral load response.
Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other.
Outcome Abacavir 600 mg q.d. plus EPIVIR®** plus Efavirenz (n = 384) Abacavir 300 mg b.i.d. plus EPIVIR®** plus Efavirenz (n = 386)
Responder * 64% (71%) 65% (72%)
Virologic failures 11% (5%) 11% (5%)
Discontinued due to adverse reactions 13% 11%
Discontinued due to other reasons 11% 13%

After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm3 in the group receiving abacavir 600 mg once daily and 200 cells/mm3 in the group receiving abacavir 300 mg twice daily. Through Week 48, six subjects (2%) in the group receiving abacavir 600 mg once daily (four CDC classification C events and two deaths) and ten subjects (3%) in the group receiving abacavir 300 mg twice daily (seven CDC classification C events and three deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.

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