Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations.
ATC code: J05AR03
Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Both emtricitabine and tenofovir have activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain termination.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.
Synergistic antiviral activity was observed with the combination of emtricitabine and tenofovir in vitro. Additive to synergistic effects were observed in combination studies with protease inhibitors, and with nucleoside and non-nucleoside analogue inhibitors of HIV reverse transcriptase.
Resistance has been seen in vitro and in some HIV-1 infected patients due to the development of the M184V/I mutation with emtricitabine or the K65R mutation with tenofovir. Emtricitabine-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and zidovudine. The K65R mutation can also be selected by abacavir or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the K65R mutation. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine and tenofovir. HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil.
In an open-label randomised clinical study (GS-01-934) in antiretroviral-naïve patients, genotyping was performed on plasma HIV-1 isolates from all patients with confirmed HIV RNA >400 copies/mL at weeks 48, 96 or 144 or at the time of early study drug discontinuation. As of week 144:
Plasma samples from 2 clinical studies of HIV-1 uninfected subjects, iPrEx and Partners PrEP, were analysed for 4 HIV-1 variants expressing amino acid substitutions (i.e. K65R, K70E, M184V, and M184I) that potentially confer resistance to tenofovir or emtricitabine. In the iPrEx clinical study, no HIV-1 variants expressing K65R, K70E, M184V, or M184I were detected at the time of seroconversion among subjects who became infected with HIV-1 after enrollment in the study. In 3 of 10 subjects who had acute HIV infection at study enrollment, M184I and M184V mutations were detected in the HIV of 2 of 2 subjects in the Truvada group and 1 of 8 subjects in the placebo group.
In the Partners PrEP clinical study, no HIV-1 variants expressing K65R, K70E, M184V, or M184I were detected at the time of seroconversion among subjects who became infected with HIV-1 during the study. In 2 of 14 subjects who had acute HIV infection at study enrollment, the K65R mutation was detected in the HIV of 1 of 5 subjects in the tenofovir disoproxil 245 mg group and the M184V mutation (associated with resistance to emtricitabine) was detected in the HIV of 1 of 3 subjects in the Truvada group.
In an open-label randomised clinical study (GS-01-934), antiretroviral-naïve HIV-1 infected adult patients received either a once daily regimen of emtricitabine, tenofovir disoproxil and efavirenz (n=255) or a fixed combination of lamivudine and zidovudine administered twice daily and efavirenz once daily (n=254). Patients in the emtricitabine and tenofovir disoproxil group were given Truvada and efavirenz from week 96 to week 144. At baseline the randomised groups had similar median plasma HIV-1 RNA (5.02 and 5.00 log10 copies/mL) and CD4 counts (233 and 241 cells/mm³). The primary efficacy endpoint for this study was the achievement and maintenance of confirmed HIV-1 RNA concentrations <400 copies/mL over 48 weeks. Secondary efficacy analyses over 144 weeks included the proportion of patients with HIV-1 RNA concentrations <400 or <50 copies/mL, and change from baseline in CD4 cell count.
The 48-week primary endpoint data showed that the combination of emtricitabine, tenofovir disoproxil and efavirenz provided superior antiviral efficacy as compared with the fixed combination of lamivudine and zidovudine with efavirenz as shown in Table 4. The 144 week secondary endpoint data are also presented in Table 4.
Table 4. 48- and 144-week efficacy data from study GS-01-934 in which emtricitabine, tenofovir disoproxil and efavirenz were administered to antiretroviral-naïve patients with HIV-1 infection:
| GS-01-934 Treatment for 48 weeks | GS-01-934 Treatment for 144 weeks | |||
|---|---|---|---|---|
| Emtricitabine+tenofovir disoproxil+efavirenz | Lamivudine+zidovudine+efavirenz | Emtricitabine+tenofovir disoproxil+efavirenz* | Lamivudine+zidovudine+efavirenz | |
| HIV-1 RNA <400 copies/mL (TLOVR) | 84% (206/244) | 73% (177/243) | 71% (161/227) | 58% (133/229) |
| p-value | 0,002** | 0,004** | ||
| % difference (95%CI) | 11% (4% to 19%) | 13% (4% to 22%) | ||
| HIV-1 RNA <50 copies/mL (TLOVR) | 80% (194/244) | 70% (171/243) | 64% (146/227) | 56% (130/231) |
| p-value | 0,021** | 0,082** | ||
| % difference (95%CI) | 9% (2% to 17%) | 8% (-1% to 17%) | ||
| Mean change from baseline in CD4 cell count (cells/mm3) | +190 | +158 | +312 | +271 |
| p-value | 0,002a | 0,089a | ||
| Difference (95%CI) | 32 (9 to 55) | 41 (4 to 79) | ||
* Patients receiving emtricitabine, tenofovir disoproxil and efavirenz were given Truvada plus efavirenz from week 96 to 144.
** The p-value based on the Cochran-Mantel-Haenszel Test stratified for baseline CD4 cell count
TLOVR = Time to Loss of Virologic Response
a Van Elteren Test
In a randomised clinical study (M02-418), 190 antiretroviral-naïve adults were treated once daily with emtricitabine and tenofovir disoproxil in combination with lopinavir/ritonavir given once or twice daily. At 48 weeks, 70% and 64% of patients demonstrated HIV-1 RNA <50 copies/mL with the once and twice daily regimens of lopinavir/ritonavir, respectively. The mean changes in CD4 cell count from baseline were +185 cells/mm³ and +196 cells/mm³, respectively.
Limited clinical experience in patients co-infected with HIV and HBV suggests that treatment with emtricitabine or tenofovir disoproxil in antiretroviral combination therapy to control HIV infection results in a reduction in HBV DNA (3 log10 reduction or 4 to 5 log10 reduction, respectively) (see section 4.4).
The iPrEx study (CO-US-104-0288) evaluated Truvada or placebo in 2,499 HIV-uninfected men (or transgender women) who have sex with men and who were considered at high risk for HIV infection. Subjects were followed for 4,237 person-years. Baseline characteristics are summarised in Table 5.
Table 5. Study population from study CO-US-104-0288 (iPrEx):
| Placebo (n=1248) | Truvada (n=1251) | |
|---|---|---|
| Age (Yrs), Mean (SD) | 27 (8,5) | 27 (8,6) |
| Race, N (%) | ||
| Black/African American | 97 (8) | 117 (9) |
| White | 208 (17) | 223 (18) |
| Mixed/Other | 878 (70) | 849 (68) |
| Asian | 65 (5) | 62 (5) |
| Hispanic/Latino Ethnicity, N (%) | 906 (73) | 900 (72) |
| Sexual Risk Factors at Screening | ||
| Number of Partners Previous 12 Weeks, Mean (SD) | 18 (43) | 18 (35) |
| URAI Previous 12 Weeks, N (%) | 753 (60) | 732 (59) |
| URAI with HIV+ (or unknown status) Partner Previous 6 Mos, N (%) | 1009 (81) | 992 (79) |
| Involved in Transactional Sex Last 6 Month, N (%) | 510 (41) | 517 (41) |
| Known HIV+ Partner Last 6 Months, N (%) | 32 (3) | 23 (2) |
| Syphilis Seroreactivity, N (%) | 162/1239 (13) | 164/1240 (13) |
| Serum Herpes Simplex Virus Type 2 Infection, N (%) | 430/1243 (35) | 458/1241 (37) |
| Urine Leukocyte Esterase Positive, N (%) | 22 (2) | 23 (2) |
URAI = unprotected receptive anal intercourse
The incidences of HIV seroconversion overall and in the subset reporting unprotected receptive anal intercourse are shown in Table 6. Efficacy was strongly correlated with adherence as assessed by detection of plasma or intracellular drug levels in a case-control study (Table 7).
Table 6. Efficacy in study CO-US-104-0288 (iPrEx):
| Placebo | Truvada | P-valuea,b | |
|---|---|---|---|
| mITT Analysis | |||
| Seroconversions / N | 83 / 1217 | 48 / 1224 | 0,002 |
| Relative Risk Reduction (95% CI)b | 42% (18%, 60%) | ||
| URAI Within 12 Weeks Prior to Screening, mITT Analysis | |||
| Seroconversions / N | 72 / 753 | 34 / 732 | 0,0349 |
| Relative Risk Reduction (95% CI)b | 52% (28%, 68%) | ||
a P-values by logrank test. P-values for URAI refer to the null hypothesis that efficacy differed between subgroup strata (URAI, no URAI).
b Relative risk reduction calculated for mITT based on incident seroconversion, ie, occurring post-baseline through first post-treatment visit (approximately 1 month after last study drug dispensation).
Table 7. Efficacy and adherence in study CO-US-104-0288 (iPrEx, matched case-control analysis):
| Cohort | Drug Detected | Drug Not Detected | Relative Risk Reduction (2-sided 95% CIa |
|---|---|---|---|
| HIV-Positive Subjects | 4 (8%) | 44 (92%) | 94% (78%, 99%) |
| HIV-Negative Matched Control Subjects | 63 (44%) | 81 (56%) | - |
a Relative risk reduction calculated on incident (post-baseline) seroconversion from the double-blind treatment period and through the 8-week follow-up period. Only samples from subjects randomized to Truvada were evaluated for detectable plasma or intracellular tenofovir disoproxil-DP levels.
The Partners PrEP clinical study (CO-US-104-0380) evaluated Truvada, tenofovir disoproxil 245 mg, or placebo in 4,758 HIV-uninfected subjects from Kenya or Uganda in serodiscordant heterosexual couples. Subjects were followed for 7,830 person-years. Baseline characteristics are summarised in Table 8.
Table 8. Study population from study CO-US-104-0380 (Partners PrEP):
| Placebo (n=1584) | Tenofovir disoproxil 245 mg (n=1584) | Truvada (n=1579) | |
|---|---|---|---|
| Age (Yrs), Median (Q1, Q3) | 34 (28, 40) | 33 (28, 39) | 33 (28, 40) |
| Gender, N (%) | |||
| Male | 963 (61) | 986 (62) | 1013 (64) |
| Female | 621 (39) | 598 (38) | 566 (36) |
| Key Couple Characteristics, N (%) or Median (Q1, Q3) | |||
| Married to study partner | 1552 (98) | 1543 (97) | 1540 (98) |
| Years living with study partner | 7,1 (3,0, 14,0) | 7,0 (3,0, 13,5) | 7,1 (3,0, 14,0) |
| Years aware of discordant status | 0,4 (0,1, 2,0) | 0,5 (0,1, 2,0) | 0,4 (0,1, 2,0) |
The incidence of HIV seroconversion is shown in Table 9. The rate of HIV-1 seroconversion in males was 0.24/100 person-years of Truvada exposure and the rate of HIV-1 seroconversion in females was 0.95/100 person-years of Truvada exposure. Efficacy was strongly correlated with adherence as assessed by detection of plasma or intracellular drug levels and was higher among substudy participants who received active adherence counselling and as show in Table 10.
Table 9. Efficacy in study CO-US-104-0380 (Partners PrEP):
| Placebo | Tenofovir disoproxil 245 mg | Truvada | |
|---|---|---|---|
| Seroconversions / Na | 52 / 1578 | 17 / 1579 | 13 / 1576 |
| Incidence per 100 person-years (95% CI) | 1,99 (1,49, 2,62) | 0,65 (0,38, 1,05) | 0,50 (0,27, 0,85) |
| Relative Risk Reduction (CI 95%) | — | 67% (44%, 81%) | 75% (55%, 87%) |
a Relative risk reduction calculated for mITT cohort based on incident (post-baseline) seroconversion. Comparisons for active study groups are made versus placebo.
Table 10. Efficacy and adherence in study CO-US-104-0380 (Partners PrEP):
| Study Drug Quantification | Number with Tenofovir Detected/Total Samples (%) | Risk Estimate for HIV-1 Protection: Detection Versus No Detection of Tenofovir | ||
|---|---|---|---|---|
| Case | Cohort | Relative Risk Reduction (CI 95%) | p-value | |
| FTC/tenofovir disoproxil Groupa | 3 / 12 (25%) | 375 / 465 (81%) | 90% (56%, 98%) | 0,002 |
| Tenofovir disoproxil Groupa | 6 / 17 (35%) | 363 / 437 (83%) | 86% (67%, 95%) | <0,001 |
| Adherence Substudy | Adherence Substudy Participantsb | |||
| Placebo | Tenofovir disoproxil 245 mg +Truvada | Relative Risk Reduction (CI 95%) | p-value | |
| Seroconversions / Nb | 14 / 404 (3,5%) | 0 / 745 (0%) | 100% (87%, 100%) | <0,001 |
a ‘Case’ = HIV seroconverter; ‘Cohort’ = 100 randomly selected subjects from each of the tenofovir disoproxil 245 mg and Truvada groups. Only Case or Cohort samples from subjects randomised to either tenofovir disoproxil 245 mg or Truvada were evaluated for detectable plasma tenofovir levels.
b Substudy participants received active adherence monitoring, e.g. unannounced home visits and pill counts, and counselling to improve compliance with study drug.
The safety and efficacy of Truvada in children under the age of 12 years have not been established.
There are no clinical studies conducted with Truvada in the paediatric population with HIV-1 infection.
Clinical efficacy and safety of Truvada was established from studies conducted with emtricitabine and tenofovir disoproxil when given as single agents.
In infants and children older than 4 months, the majority of patients taking emtricitabine achieved or maintained complete suppression of plasma HIV-1 RNA through 48 weeks (89% achieved ≤400 copies/mL and 77% achieved ≤50 copies/mL).
In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to <18 years of age were treated with tenofovir disoproxil (n=45) or placebo (n=42) in combination with an optimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at week 24. However, a benefit is expected for the adolescent population based on extrapolation of adult data and comparative pharmacokinetic data (see section 5.2).
In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, respectively, at baseline. Mean changes at week 48 (end of double-blind phase) were -0.215 and – 0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxil and placebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil group compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD loss (defined as >4% loss). Among 28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body.
In study GS-US-104-0352, 97 treatment-experienced patients 2 to <12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil treatment group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations <400 copies/mL. The difference in the proportion of patients who maintained <400 copies/mL at week 48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil treatment group. When missing data were excluded, 91% of patients in the tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations <400 copies/mL at week 48.
Reductions in BMD have been reported in paediatric patients. In patients who received treatment with tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and -0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline. Mean changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or zidovudine groups, respectively. The mean rate of lumbar spine bone gain at week 48 was similar between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group. Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine or zidovudine treatment group. One tenofovir disoproxil treated subject and no stavudine or zidovudine treated subjects experienced significant (>4%) lumbar spine BMD loss at week 48. BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil for 96 weeks. BMD Z-scores were not adjusted for height and weight.
In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy (median tenofovir disoproxil exposure 331 weeks).
The efficacy and safety of Truvada for pre-exposure prophylaxis in adolescents who adhere to daily dosing is expected to be similar to that in adults at the same level of adherence. The potential renal and bone effects with long-term use of Truvada for pre-exposure prophylaxis in adolescents are uncertain (see section 4.4).
The bioequivalence of one Truvada film-coated tablet with one emtricitabine 200 mg hard capsule and one tenofovir disoproxil 245 mg film-coated tablet was established following single dose administration to fasting healthy subjects. Following oral administration of Truvada to healthy subjects, emtricitabine and tenofovir disoproxil are rapidly absorbed and tenofovir disoproxil is converted to tenofovir. Maximum emtricitabine and tenofovir concentrations are observed in serum within 0.5 to 3.0 h of dosing in the fasted state. Administration of Truvada with food resulted in a delay of approximately three quarters of an hour in reaching maximum tenofovir concentrations and increases in tenofovir AUC and Cmax of approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In order to optimise the absorption of tenofovir, it is recommended that Truvada should preferably be taken with food.
Following intravenous administration the volume of distribution of emtricitabine and tenofovir was approximately 1.4 L/kg and 800 mL/kg, respectively. After oral administration of emtricitabine or tenofovir disoproxil, emtricitabine and tenofovir are widely distributed throughout the body. In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02 to 200 µg/mL. In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL.
There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation. Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. The apparent clearance of tenofovir averaged approximately 307 mL/min. Renal clearance has been estimated to be approximately 210 mL/min, which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.
Pharmacokinetic studies have not been performed with emtricitabine or tenofovir (administered as tenofovir disoproxil) in the elderly (over 65 years of age).
Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.
No clinically important pharmacokinetic difference due to ethnicity has been identified for emtricitabine. The pharmacokinetics of tenofovir (administered as tenofovir disoproxil) have not been specifically studied in different ethnic groups.
Pharmacokinetic studies have not been performed with Truvada in children and adolescents (under 18 years of age). Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to <18 years) with body weight ≥35 kg and in 23 HIV-1 infected children aged 2 to <12 years. Tenofovir exposure achieved in these paediatric patients receiving oral daily doses of tenofovir disoproxil 245 mg or 6.5 mg/kg body weight tenofovir disoproxil up to a maximum dose of 245 mg was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg. Pharmacokinetic studies have not been performed with tenofovir disoproxil in children under 2 years. In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months up to 18 years) are similar to those seen in adults.
The pharmacokinetics of emtricitabine and tenofovir (administered as tenofovir disoproxil) are expected to be similar in HIV-1 infected and uninfected adolescents based on the similar exposures of emtricitabine and tenofovir in HIV-1 infected adolescents and adults, and the similar exposures of emtricitabine and tenofovir in HIV-1 infected and uninfected adults.
Limited pharmacokinetic data are available for emtricitabine and tenofovir after co-administration of separate preparations or as Truvada in patients with renal impairment. Pharmacokinetic parameters were mainly determined following administration of single doses of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected subjects with varying degrees of renal impairment. The degree of renal impairment was defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl >80 mL/min; mild impairment with CrCl = 50-79 mL/min; moderate impairment with CrCl = 30-49 mL/min and severe impairment with CrCl = 10-29 mL/min).
The mean (CV) emtricitabine drug exposure increased from 12 (25) µg•h/mL in subjects with normal renal function, to 20 (6%) µg•h/mL, 25 (23%) µg•h/mL and 34 (6%) µg•h/mL, in subjects with mild, moderate and severe renal impairment, respectively. The mean (CV) tenofovir drug exposure increased from 2,185 (12) ng•h/mL in subjects with normal renal function, to 3,064 (30%) ng•h/mL, 6,009 (42%) ng•h/mL and 15,985 (45%) ng•h/mL, in subjects with mild, moderate and severe renal impairment, respectively.
The increased dose interval for Truvada in HIV-1 infected patients with moderate renal impairment is expected to result in higher peak plasma concentrations and lower Cmin levels as compared to patients with normal renal function. In subjects with end-stage renal disease (ESRD) requiring haemodialysis, between dialysis drug exposures substantially increased over 72 hours to 53 (19%) µg•h/mL of emtricitabine, and over 48 hours to 42,857 (29%) ng•h/mL of tenofovir.
A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics of tenofovir disoproxil in combination with emtricitabine in HIV infected patients with renal impairment.
A subgroup of patients with baseline creatinine clearance between 50 and 60 mL/min, receiving once daily dosing, had a 2-4-fold increase in tenofovir exposure and worsening renal function.
The pharmacokinetics of emtricitabine and tenofovir (administered as tenofovir disoproxil) in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations (see sections 4.2 and 4.4).
The pharmacokinetics of Truvada have not been studied in subjects with hepatic impairment.
The pharmacokinetics of emtricitabine have not been studied in non-HBV infected subjects with varying degrees of hepatic insufficiency. In general, emtricitabine pharmacokinetics in HBV infected subjects were similar to those in healthy subjects and in HIV infected patients.
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected subjects with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (CV) tenofovir Cmax and AUC0-∞ values were 223 (34.8) ng/mL and 2,050 (50.8%) ng•h/mL, respectively, in normal subjects compared with 289 (46.0%) ng/mL and 2,310 (43.5%) ng•h/mL in subjects with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ng•h/mL in subjects with severe hepatic impairment.
Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
Non-clinical safety pharmacology studies on tenofovir disoproxil reveal no special hazard for humans. Repeated dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced BMD (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures ≥5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.
Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay.
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice. These tumours are unlikely to be of relevance to humans.
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a periand postnatal toxicity study at maternally toxic doses.
Genotoxicity and repeated dose toxicity studies of one month or less with the combination of these two components found no exacerbation of toxicological effects compared to studies with the separate components.
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