CLINICAL PHARMACOLOGY
Mechanism of Action
Etravirine is an antiviral drug [ see Clinical Pharmacology ].
Pharmacodynamics
Effects on Electrocardiogram
In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered INTELENCE™ 200 mg b.i.d., INTELENCE™ 400 mg q.d., placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg b.i.d. and -1.0 ms (2.5 ms) for 400 mg q.d. dosing regimens.
Pharmacokinetics
Pharmacokinetics in Adults
The pharmacokinetic properties of INTELENCE™ were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects than in healthy subjects.
Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Subjects (Integrated Data from Phase 3 Trials at Week 24)All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 5 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of INTELENCE™ with darunavir/ritonavir. | Parameter | Etravirine 200 mg b.i.d.
N = 574 |
| AUC12h (ng∙h/mL) | |
| Geometric Mean ± Standard Deviation | 4531.53 ± 4543.69 |
| Median (Interquartile Range) | 4450.7 (3091.3 - 6315.0) |
| C0h (ng/mL) | |
| Geometric Mean ± Standard Deviation | 296.74 ± 377.52 |
| Median (Interquartile Range) | 298.8 (188.5 - 462.3) |
Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro = 4 ng/mL.
Absorption and Bioavailability
Following oral administration, etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of INTELENCE™ is unknown.
In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.
Effects of Food on Oral Absorption
The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE™ was administered under fasting conditions, as compared to when INTELENCE™ was administered following a meal. Therefore, INTELENCE™ should always be taken following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat). [ see Dosage and Administration (2) ].
Distribution
Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66%-99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
Metabolism
In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A4, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.
Elimination
After single dose oral administration of 800 mg 14C-etravirine, 93.7% and 1.2% of the administered dose of 1 4C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.
Special Populations
Hepatic Impairment
Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE™ to subjects with normal hepatic function (n = 16), mild hepatic impairment (Child-Pugh Class A, n = 8), and moderate hepatic impairment (Child-Pugh Class B, n = 8). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated.
Hepatitis B and/or Hepatitis C Virus Co-infection
Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile [ see Adverse Reactions (6) ], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.
Renal Impairment
The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that <1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Gender
No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in clinical studies.
Race
Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.
Geriatric Patients
Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [ see Use in Specific Populations ].
Pediatric Patients
The pharmacokinetics of etravirine in pediatric patients have not been evaluated. Dosing recommendations for pediatric patients cannot be made due to insufficient data.
Drug Interactions
[ See also Drug Interactions (7) .]
Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE™ with drugs that induce or inhibit CYP3A4, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE™.
Etravirine is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Therefore, co-administration of drugs that are substrates of CYP3A4, CYP2C9 and CYP2C19 with INTELENCE™ may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).
Drug interaction studies were performed with INTELENCE™ and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table 6 (effect of other drugs on INTELENCE™). The effect of co-administration of INTELENCE™ on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 7 (effect of INTELENCE™ on other drugs). For information regarding clinical recommendations, see Drug Interactions (7) .
Table 6: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs | Co-administered Drug | Dose/Schedule of Co-administered Drug | N | Exposure | Mean Ratio of Etravirine
Pharmacokinetic Parameters
90% CI; No Effect = 1.00 |
| Cmax | AUC | Cmin |
| CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily; q.a.m. = once daily in the morning |
| Co-Administration With Protease Inhibitors (PIs) |
| Atazanavir | 400 mg q.d. | 14 | ↑ | 1.47
(1.36-1.59) | 1.50
(1.41-1.59) | 1.58
(1.46-1.70) |
Atazanavir/
ritonavir | 300/100 mg q.d. | 14 | ↑ | 1.30
(1.17-1.44) | 1.30
(1.18-1.44) | 1.26
(1.12-1.42) |
Darunavir/
ritonavir | 600/100 mg b.i.d. | 14 | ↓ | 0.68
(0.57-0.82) | 0.63
(0.54-0.73) | 0.51
(0.44-0.61) |
Lopinavir/
ritonavir
(melt extrusion tablet) | 400/100 mg b.i.d. | 16 | ↓ | 0.70
(0.64-0.78) | 0.65
(0.59-0.71) | 0.55
(0.49-0.62) |
| Ritonavir | 600 mg b.i.d. | 11 | ↓ | 0.68
(0.55-0.85) | 0.54
(0.41-0.73) | N.A. |
Saquinavir/
ritonavir
| 1000/100 mg b.i.d. | 14 | ↓ | 0.63
(0.53-0.75) | 0.67
(0.56-0.80) | 0.71
(0.58-0.87) |
Tipranavir/
ritonavir | 500/200 mg b.i.d. | 19 | ↓ | 0.29
(0.22-0.40) | 0.24
(0.18-0.33) | 0.18
(0.13-0.25) |
| Co-Administration With Nucleoside Reverse Transcriptase Inhibitors (NRTIs) |
| Didanosine | 400 mg q.d. | 15 | ↔ | 1.16
(1.02-1.32) | 1.11
(0.99-1.25) | 1.05
(0.93-1.18) |
| Tenofovir disoproxil fumarate | 300 mg q.d. | 23 | ↓ | 0.81
(0.75-0.88) | 0.81
(0.75-0.88) | 0.82
(0.73-0.91) |
| Co-Administration With Integrase Strand Transfer Inhibitors |
| Raltegravir | 400 mg b.i.d. | 19 | ↔ | 1.04
(0.97-1.12) | 1.10
(1.03-1.16) | 1.17
(1.10-1.26) |
| Co-Administration With Other Drugs |
| Atorvastatin | 40 mg q.d. | 16 | ↔ | 0.97
(0.93-1.02) | 1.02
(0.97-1.07) | 1.10
(1.02-1.19) |
| Clarithromycin | 500 mg b.i.d. | 15 | ↑ | 1.46
(1.38-1.56) | 1.42
(1.34-1.50) | 1.46
(1.36-1.58) |
| Fluconazole | 200 mg q.a.m. | 16 | ↑ | 1.75
(1.60-1.91) | 1.86
(1.73-2.00) | 2.09
(1.90-2.31) |
| Omeprazole | 40 mg q.d. | 18 | ↑ | 1.17
(0.96-1.43) | 1.41
(1.22-1.62) | N.A. |
| Paroxetine | 20 mg q.d. | 16 | ↔ | 1.05
(0.96-1.15) | 1.01
(0.93-1.10) | 1.07
(0.98-1.17) |
| Ranitidine | 150 mg b.i.d. | 18 | ↓ | 0.94
(0.75-1.17) | 0.86
(0.76-0.97) | N.A. |
| Rifabutin | 300 mg q.d. | 12 | ↓ | 0.63
(0.53-0.74) | 0.63
(0.54-0.74) | 0.65
(0.56-0.74) |
| Voriconazole | 200 mg b.i.d. | 16 | ↑ | 1.26
(1.16-1.38) | 1.36
(1.25-1.47) | 1.52
(1.41-1.64) |
Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of INTELENCE™ | Co-administered Drug | Dose/Schedule of Co-administered Drug | N | Exposure | Mean Ratio of
Co-administered Drug
Pharmacokinetic Parameters
90% CI; No Effect = 1.00 |
| Cmax | AUC | Cmin |
| CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily; q.a.m. = once daily in the morning |
| Co-Administration With Protease Inhibitors (PIs) |
| Atazanavir | 400 mg q.d. | 14 | ↓ | 0.97
(0.73-1.29) | 0.83
(0.63-1.09) | 0.53
(0.38-0.73) |
Atazanavir/
ritonavir | 300/100 mg q.d. | 13 | ↓ | 0.97
(0.89-1.05) | 0.86
(0.79-0.93) | 0.62
(0.55-0.71) |
Darunavir/
ritonavir | 600/100 mg b.i.d. | 15 | ↔ | 1.11
(1.01-1.22) | 1.15
(1.05-1.26) | 1.02
(0.90-1.17) |
Fosamprenavir/
ritonavir | 700/100 mg b.i.d. | 8 | ↑ | 1.62
(1.47-1.79) | 1.69
(1.53-1.86) | 1.77
(1.39-2.25) |
Lopinavir/
ritonavir
(melt extrusion tablet) | 400/100 mg b.i.d. | 16 | ↔ | 0.89
(0.82-0.96) | 0.87
(0.83-0.92) | 0.80
(0.73-0.88) |
Saquinavir/
ritonavir | 1000/100 mg b.i.d. | 15 | ↔ | 1.00
(0.70-1.42) | 0.95
(0.64-1.42) | 0.80
(0.46-1.38) |
Tipranavir/
ritonavir | 500/200 mg b.i.d. | 19 | ↑ | 1.14
(1.02-1.27) | 1.18
(1.03-1.36) | 1.24
(0.96-1.59) |
| Co-Administration With Nucleoside Reverse Transcriptase Inhibitors (NRTIs) |
| Didanosine | 400 mg q.d. | 14 | ↔ | 0.91
(0.58-1.42) | 0.99
(0.79-1.25) | N.A. |
| Tenofovir disoproxil fumarate | 300 mg q.d. | 19 | ↔ | 1.15
(1.04-1.27) | 1.15
(1.09-1.21) | 1.19
(1.13-1.26) |
| Co-Administration With Integrase Strand Transfer Inhibitors |
| Raltegravir | 400 mg b.i.d. | 19 | ↓ | 0.89
(0.68-1.15) | 0.90
(0.68-1.18) | 0.66
(0.34-1.26) |
| Co-Administration With Other Drugs |
| Atorvastatin | 40 mg q.d. | 16 | ↓ | 1.04
(0.84-1.30) | 0.63
(0.58-0.68) | N.A. |
| | | | | | | |
| 2-hydroxy-atorvastatin | | 16 | ↑ | 1.76
(1.60-1.94) | 1.27
(1.19-1.36) | N.A. |
| Clarithromycin | 500 mg b.i.d. | 15 | ↓ | 0.66
(0.57-0.77) | 0.61
(0.53-0.69) | 0.47
(0.38-0.57) |
| | | | | | | |
| 14-hydroxy-clarithromycin | | 15 | ↑ | 1.33
(1.13-1.56) | 1.21
(1.05-1.39) | 1.05
(0.90-1.22) |
| Ethinylestradiol | 0.035 mg q.d. | 16 | ↑ | 1.33
(1.21-1.46) | 1.22
(1.13-1.31) | 1.09
(1.01-1.18) |
| | | | | | | |
| Norethindrone | 1 mg q.d. | 16 | ↔ | 1.05
(0.98-1.12) | 0.95
(0.90-0.99) | 0.78
(0.68-0.90) |
| Fluconazole | 200 mg q.a.m. | 15 | ↔ | 0.92
(0.85-1.00) | 0.94
(0.88-1.01) | 0.91
(0.84-0.98) |
| R(-) Methadone | Individual dose regimen ranging from 60 to 130 mg/day | 16 | ↔ | 1.02
(0.96-1.09) | 1.06
(0.99-1.13) | 1.10
(1.02-1.19) |
| | | | | | | |
| S(+) Methadone | | 16 | ↔ | 0.89
(0.83-0.97) | 0.89
(0.82-0.96) | 0.89
(0.81-0.98) |
| Paroxetine | 20 mg q.d. | 16 | ↔ | 1.06
(0.95-1.20) | 1.03
(0.90-1.18) | 0.87
(0.75-1.02) |
| Rifabutin | 300 mg q.d. | 12 | ↓ | 0.90
(0.78-1.03) | 0.83
(0.75-0.94) | 0.76
(0.66-0.87) |
| | | | | | | |
| 25- O -desacetylrifabutin | 300 mg q.d. | 12
| ↓ | 0.85
(0.72-1.00) | 0.83
(0.74-0.92) | 0.78
(0.70-0.87) |
| Sildenafil | 50 mg single dose | 15 | ↓ | 0.55
(0.40-0.75) | 0.43
(0.36-0.51) | N.A. |
| | | | | | | |
| N-desmethyl-sildenafil | | 15 | ↓ | 0.75
(0.59-0.96) | 0.59
(0.52-0.68) | N.A. |
| Voriconazole | 200 mg b.i.d. | 14 | ↑ | 0.95
(0.75-1.21) | 1.14
(0.88-1.47) | 1.23
(0.87-1.75) |
Microbiology
Mechanism of Action
Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases alpha, beta, and γ.
Antiviral Activity in Cell Culture
Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC50 values ranging from 0.29 to 1.65 nM and EC50 values ranging from 11.5 to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs—the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; and the fusion inhibitor enfuvirtide (ENF).
Resistance
In Cell Culture
Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.
In Treatment-Experienced Subjects
In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 24 to the INTELENCE™-containing regimen were V179F, V179I, Y181C, and Y181I which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE™ in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance associated substitutions which emerged on etravirine treatment in < 10% of the virologic failure isolates included K101E, K103N, V106I/M, V108I, Y188L, V189I, G190S/C and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.
Cross-Resistance
Site-Directed NNRTI Mutant Virus
Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility > 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC50 value) and Y181V (17-fold change in EC50 value). Mutant strains containing a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change > 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).
Clinical Isolate s
Etravirine retained a fold-change ≤ 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125-C206 and TMC125-C216, 35% of the baseline isolates had decreased susceptibility to etravirine (fold-change > 3) and 61%, 71%, and 79% of these isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen for the virologic failure isolates.
Baseline Genotype/Phenotype and Virologic Outcome Analyses
In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions V179D, V179F, V179T, Y181V, or G190S was associated with a decreased virologic response to etravirine. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE™ arm. Response rates to etravirine decreased as the number of baseline NNRTI mutations increased. The presence at baseline of 3 or more IAS-USA-defined NNRTI substitutions (2007) resulted in a decreased virologic response to INTELENCE™ (shown as the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at Week 24) (Table 8).
Table 8: Proportion of Subjects with < 50 HIV-1 RNA copies/mL at Week 24 by Baseline Number of IAS-USA-Defined NNRTI Mutations in the As-Treated Population of Pooled TMC125-C206 and TMC125-C216 Trials | # IAS-USA-Defined NNRTI2007 IAS-USA defined mutations = V90I, A98G, L100I, K101E/P, K103N, V106A/I/M, V108I, V179D/F, Y181C/I/V, Y188C/H/L, G190A/S, P225H | Etravirine Arms
N = 565 |
| Re-Used/Not Used ENF | De Novo ENF |
| All ranges | 60% (251/420) | 70% (102/145) |
| 0 - 2 | 66% (213/322) | 76% (80/105) |
| ≥ 3 | 39% (38/98) | 55% (22/40) |
| | Placebo Arms
N = 593 |
| All ranges | 34% (149/434) | 62% (99/159) |
Response rates assessed by baseline etravirine phenotype are shown in Table 9. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for INTELENCE™. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients.
Table 9: Proportion of Subjects with < 50 HIV-1 RNA copies/mL at Week 24 by Baseline Phenotype and ENF Use in the Pooled TMC125-C206 and TMC125-C216 TrialsAs-treated analysis | Etravirine Fold Change | Etravirine Arms
N = 561 |
| Re-Used/Not Used ENF | De Novo ENF | Clinical Response Range |
| All ranges | 60% (249/416) | 70% (102/145) | Overall Response |
| 0 - 3 | 70% (190/273) | 82% (75/92) | Higher than Overall Response |
| > 3 - 13 | 47% (37/78) | 50% (19/38) | Lower than Overall Response |
| > 13 | 34% (22/65) | 53% (8/15) | Lower than Overall Response |
| | Placebo Arms
N = 593 |
| All ranges | 34% (149/434) | 62% (99/159) | |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Carcinogenicity studies of etravirine in rodents are ongoing. Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice. [ See Nonclinical Toxicology. ]
Impairment of Fertility
No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure up to the recommended human dose (400 mg/day).
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1000 mg/kg/day). In both species, no treatment-related embryo-fetal effects including malformations were observed. In addition, no treatment-related effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic drug exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day).
|
