CLINICAL PHARMACOLOGY
Mechanism of Action
Emtricitabine is an antiviral drug. [See Clinical Pharmacology]
Pharmacokinetics
Adult Subjects
The pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-1-infected individuals. Emtricitabine pharmacokinetics are similar between these populations.
Figure 1 shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV-1-infected subjects receiving EMTRIVA capsules.
Figure 1 Mean (± 95% CI) Steady-State Plasma Emtricitabine Concentrations in HIV-1-Infected Adults (N=20)
Absorption
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1-infected subjects, the (mean ± SD) steady-state plasma emtricitabine peak concentration (Cmax) was 1.8 ± 0.7 µg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 µg∙hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 µg/mL. The mean absolute bioavailability of EMTRIVA capsules was 93% while the mean absolute bioavailability of EMTRIVA oral solution was 75%. The relative bioavailability of EMTRIVA oral solution was approximately 80% of EMTRIVA capsules.
The multiple dose pharmacokinetics of emtricitabine are dose proportional over a dose range of 25–200 mg.
Distribution
In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02–200 µg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.
Metabolism
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14C-emtricitabine, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~4% of dose). No other metabolites were identifiable.
Elimination
The plasma emtricitabine half-life is approximately 10 hours. The renal clearance of emtricitabine is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption
EMTRIVA capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA oral solution was administered with either a high-fat or low-fat meal.
Special Populations
Race, Gender
The pharmacokinetics of emtricitabine were similar in adult male and female patients and no pharmacokinetic differences due to race have been identified.
Pediatric Patients
The pharmacokinetics of emtricitabine at steady state were determined in 77 HIV-1-infected children, and the pharmacokinetic profile was characterized in four age groups (Table 6). The emtricitabine exposure achieved in children receiving a daily dose of 6 mg/kg up to a maximum of 240 mg oral solution or a 200 mg capsule is similar to exposures achieved in adults receiving a once-daily dose of 200 mg.
The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 6 weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each 3 mg/kg once daily × 4 days) during the first 3 months of life. The AUC observed in neonates who received a daily dose of 3 mg/kg of emtricitabine was similar to the AUC observed in pediatric patients ≥3 months to 17 years who received a daily dose of emtricitabine as a 6 mg/kg oral solution up to 240 mg or as a 200 mg capsule (Table 6).
Table 6 Mean ± SD Pharmacokinetic Parameters by Age Groups for Pediatric Patients and Neonates Receiving EMTRIVA Capsules or Oral Solution
|
HIV-1-exposed Neonates |
HIV-1-infected Pediatric Patients |
Age |
0–3 mo (N=20)Two pharmacokinetic evaluations were conducted in 20 neonates over the first 3 months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5–81) days.
|
3–24 mo (N=14) |
25 mo–6 yr (N=19) |
7–12yr (N=17) |
13–17 yr (N=27) |
Formulation |
|
|
|
|
|
Capsule (n) |
0 |
0 |
0 |
10 |
26 |
Oral Solution (n) |
20 |
14 |
19 |
7 |
1 |
Dose (mg/kg)Mean (range)
|
3.1 (2.9–3.4) |
6.1 (5.5–6.8) |
6.1 (5.6–6.7) |
5.6 (3.1–6.6) |
4.4 (1.8–7.0) |
Cmax (µg/mL) |
1.6 ± 0.6 |
1.9 ± 0.6 |
1.9 ± 0.7 |
2.7 ± 0.8 |
2.7 ± 0.9 |
AUC (µg∙hr/mL) |
11.0 ± 4.2 |
8.7 ± 3.2 |
9.0 ± 3.0 |
12.6 ± 3.5 |
12.6 ± 5.4 |
T1/2 (hr) |
12.1 ± 3.1 |
8.9 ± 3.2 |
11.3 ± 6.4 |
8.2 ± 3.2 |
8.9 ± 3.3 |
Geriatric Patients
The pharmacokinetics of emtricitabine have not been fully evaluated in the elderly.
Patients with Impaired Renal Function
The pharmacokinetics of emtricitabine are altered in patients with renal impairment [See Warnings and Precautions]. In adult patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to a reduction in renal clearance (Table 7). It is recommended that the dosing interval for EMTRIVA be modified in adult patients with creatinine clearance <50 mL/min or in adult patients with ESRD who require dialysis [See Dosage and Administration]. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.
Table 7 Mean ± SD Pharmacokinetic Parameters in Adult Patients with Varying Degrees of Renal Function
Creatinine Clearance (mL/min) |
>80 (N=6) |
50–80 (N=6) |
30–49 (N=6) |
<30 (N=5) |
ESRDESRD patients requiring dialysis
<30 (N=5) |
Baseline creatinine clearance (mL/min) |
107 ± 21 |
59.8 ± 6.5 |
40.9 ± 5.1 |
22.9 ± 5.3 |
8.8 ± 1.4 |
Cmax (µg/mL) |
2.2 ± 0.6 |
3.8 ± 0.9 |
3.2 ± 0.6 |
2.8 ± 0.7 |
2.8 ± 0.5 |
AUC (µg∙hr/mL) |
11.8 ± 2.9 |
19.9 ± 1.2 |
25.1 ± 5.7 |
33.7± 2.1 |
53.2 ± 9.9 |
CL/F (mL/min) |
302 ± 94 |
168 ± 10 |
138 ± 28 |
99 ± 6 |
64 ± 12 |
CLr (mL/min) |
213 ± 89 |
121 ± 39 |
69 ± 32 |
30 ± 11 |
NANA = Not Applicable
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Hemodialysis: Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Patients with Hepatic Impairment
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment, however, emtricitabine is not metabolized by liver enzymes, so the impact of liver impairment should be limited.
Assessment of Drug Interactions
At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5'-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP mediated interactions involving emtricitabine with other medicinal products is low.
EMTRIVA has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), zidovudine, indinavir, famciclovir, and stavudine. Tables 8 and 9 summarize the pharmacokinetic effects of coadministered drug on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug.
Microbiology
Mechanism of Action
Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.
Antiviral Activity
The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) value for emtricitabine was in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).
The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients were administered 25–400 mg a day of EMTRIVA as monotherapy for 10–14 days. A dose-related antiviral effect was observed, with a median decrease from baseline in plasma HIV-1 RNA of 1.3 log10 at a dose of 25 mg once daily and 1.7 log10 to 1.9 log10 at a dose of 200 mg once daily or twice daily.
Resistance
Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
Emtricitabine-resistant isolates of HIV-1 have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study of treatment-naive patients treated with EMTRIVA, didanosine, and efavirenz [See Clinical Studies], viral isolates from 37.5% of patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I substitutions in the HIV-1 reverse transcriptase gene.
In a clinical study of treatment-naive patients treated with either EMTRIVA, VIREAD, and efavirenz or zidovudine/lamivudine and efavirenz [See Clinical Studies], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed patient isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed patient isolates in the lamivudine/zidovudine group. Through 144 weeks of Study 934, no patients have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross Resistance
Cross-resistance among certain nucleoside analog reverse transcriptase inhibitors has been recognized. Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained sensitivity in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In long-term oral carcinogenicity studies of emtricitabine, 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).
Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
Emtricitabine 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.
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