Original Paper Pharmacology 2014;93:166–171 DOI: 10.1159/000360639
Received: November 25, 2013 Accepted after revision: February 14, 2014 Published online: May 1, 2014
Pharmacokinetics of Single- and Multiple-Dose Emtricitabine in Healthy Male Chinese Volunteers Wen-Li Han a Jing-Chuan Shang b Bo Yan b Rui Tan a Wen-Xiang Huang d Xiao-Ni Zhong c Jun-Qing Yang a Ai-Long Huang d
Departments of a Pharmacology, b Pharmaceutical Analysis and c Epidemiology and Health Statistics, School of Public Health and Management, and d Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, PR China
Abstract Emtricitabine (FTC) is used for the treatment of HIV infection and pre-exposure chemoprophylaxis. It is often used in combination with tenofovir disoproxil fumarate (TDF). This study was designed to evaluate FTC pharmacokinetics in healthy male Chinese volunteers. Sixty subjects were recruited into this single-centre, randomised, open-label study and randomly received single (groups A, B and C) or multiple oral doses (once daily for 6 days; groups D, E and F) of 200-mg FTC capsules alone (A and D), or combined with 300-mg TDF tablets (B and E), or 200 mg of FTC plus 300 mg of TDF with a high-fat diet (C and F), respectively. FTC was well-tolerated in all groups. After a single dose, there were no differences in the mean AUC0–∞ values; however, there were significant differences in the mean Tmax values (1.05, 1.40 and 2.10 h for groups A, B and C, respectively; p < 0.05). In the multipledose study, our results were significantly different from published t1/2 values following single-dose FTC. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0031–7012/14/0934–0166$39.50/0 E-Mail [email protected] www.karger.com/pha
Introduction
Although HIV infection and AIDS have been well-controlled by effective treatment regimens in developed countries, the HIV epidemic still poses a major health problem in China, where the incidence of HIV increased by over 25% between 2001 and 2009. AIDS became China’s leading cause of death from infectious diseases for the first time in 2009 [1] while, at the same time, the HIV epidemics in sub-Saharan Africa have been largely under control [2]. Emtricitabine (FTC) is a potent nucleoside reverse transcriptase inhibitor that has been approved for the treatment of AIDS. FTC is rapidly and extensively absorbed following oral administration and its oral bioavailability is about 90% [3, 4]. Recently, pre-exposure chemoprophylaxis (PrEP) of HIV infection has gained increased momentum [5–9]. The US FDA has recommended approval of Truvada® (Gilead Sciences’ pill), the combination of FTC and tenofovir disoproxil fumarate (TDF, Viread®) for PrEP to prevent sexual transmission of HIV. FTC/TDF has been proven effective for PrEP [10]. Although the pharmacokinetics of FTC have been evaluated in both healthy and HIV-infected adults [11– 14], there are no reports from Chinese populations. Since racial differences have been observed in drug metaboProf. Junqing Yang Department of Pharmacology, Chongqing Key Laboratory of Biochemical and Molecular Pharmacology, Chongqing Medical University 1 Medical College Road, Yuzhong District, Chongqing 400016 (PR China) E-Mail junqingyang01 @ 163.com
Downloaded by: UCL 144.82.108.120 - 2/8/2017 11:24:00 AM
Key Words Pharmacokinetics · Emtricitabine · Tenofovir disoproxil fumarate · AIDS · Pre-exposure chemoprophylaxis · Healthy subjects · Chinese population
lism, there is a need to study the FTC pharmacokinetics of a Chinese population. The aim of this study was to evaluate the single- and multiple-dose pharmacokinetics of FTC for future PrEP therapy in China. Subjects, Materials and Methods Study Design This single-centre, randomised, single- and multiple-dose, open-label study was performed at the Clinical Research Centre of the First Affiliated Hospital of Chongqing Medical University (Chongqing, China), from June 2010 to December 2011. The study was conducted in compliance with the Good Clinical Practice Guideline approved by the International Conference on Harmonisation and the ethical principles of the Declaration of Helsinki [15]. The study protocol was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Chongqing Medical University (approval No. 2010010). The study’s aim, procedures and risks were thoroughly explained by clinical investigators to each of the subjects prior to them signing a consent form approved by the ethics committee. Subjects were admitted into the Centre at 8.00 p.m. the day before the study and fasted for 10 h before each drug administration. In the single-dose groups, 30 eligible subjects were randomised into three groups (10 in each group): group A received a single oral dose as a 200-mg FTC capsule; group B received a 200-mg FTC capsule and 300-mg TDF tablet, and group C received the same drugs as group B but served with a high-fat diet (40–50% fat). Drugs were administered with 200 ml of water. In the multipledose groups, another 30 eligible subjects were randomised into three groups (groups D, E and F; 10 in each group) and each group received multiple doses (once daily for 6 days) of the same regimens as group A, B and C in the single-dose study, correspondingly. All other procedures were performed in the same manner as the single-dose groups. The FTC capsules (200 mg) were manufactured and donated by Hebei Medical University Pharmaceutical Factory (Hebei, China), and the TDF tablets (300 mg) were purchased from Gilead Sciences Inc. (Foster City, Calif., USA). Inclusion/Exclusion Criteria Healthy, non-smoking Chinese males aged 20–25 years with a BMI between 19 and 24 were eligible for the study. Inclusion criteria required a healthy status confirmed by medical documentation reporting the results of a physical examination, 12-lead electrocardiography and laboratory tests (serum chemistry, haematology, urinalysis and serology tests). A subject was considered ineligible if he had a history or evidence of neurological, renal, endocrine, cardiovascular, gastrointestinal, hepatic or hematologic abnormality, any acute or chronic disease, or any drug allergy, and any disorder that might interfere with drug absorption, distribution, metabolism or excretion. Eligible subjects were compensated for their participation.
drug dosing and at the same time points as in the single-dose study after the last dosing. All blood samples were immediately centrifuged and plasma samples stored at –20 ° C until analysis [16].
Assessment of Tolerability The tolerability was assessed by monitoring vital signs, blood pressure and heart rate at baseline and at 1, 2, 4 and 6 h after dosing. Physical examinations, 12-lead electrocardiography and clinical laboratory tests were used to determine adverse events, which were collected by spontaneous reporting by the subjects or by investigator inquiries. Analysis of Plasma FTC Plasma concentrations of FTC were assessed using an HPLCUV method [17]. We added 300 μl of plasma sample spiked with internal standard lamivudine and 180 μl of 10% trichloroacetic acid into a 1.5-ml Eppendorf tube. After vortexes, the mixture was centrifuged and the supernatant was neutralised with 1% NaOH and loaded onto preconditioned Bond Elut C-18 solid-phase extraction cartridges. The FTC and lamivudine were eluted with methanol and the eluent was evaporated and reconstituted by mobile phase [20 mM KH2PO4 containing 0.08% triethylamine (pH 3.5, adjusted with H3PO4) and methanol (90:10, v/v)]. Afterwards, aliquots of 100 μl were injected onto the HPLC-UV system. The analyses were conducted at 35 ° C with a detection wavelength of 279 nm. Following FDA guidelines, the method was validated for linearity, recovery, precision, accuracy, stability, matrix effect and selectivity. The calibration curves of FTC were in good linearity within the range of 10–4,000 ng/ml. The lower limit of quantitation of FTC was 7 ng/ml. The average accuracy and intraday precision were 103.30 and
Received: November 25, 2013 Accepted after revision: February 14, 2014 Published online: May 1, 2014
Pharmacokinetics of Single- and Multiple-Dose Emtricitabine in Healthy Male Chinese Volunteers Wen-Li Han a Jing-Chuan Shang b Bo Yan b Rui Tan a Wen-Xiang Huang d Xiao-Ni Zhong c Jun-Qing Yang a Ai-Long Huang d
Departments of a Pharmacology, b Pharmaceutical Analysis and c Epidemiology and Health Statistics, School of Public Health and Management, and d Institute for Viral Hepatitis, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, PR China
Abstract Emtricitabine (FTC) is used for the treatment of HIV infection and pre-exposure chemoprophylaxis. It is often used in combination with tenofovir disoproxil fumarate (TDF). This study was designed to evaluate FTC pharmacokinetics in healthy male Chinese volunteers. Sixty subjects were recruited into this single-centre, randomised, open-label study and randomly received single (groups A, B and C) or multiple oral doses (once daily for 6 days; groups D, E and F) of 200-mg FTC capsules alone (A and D), or combined with 300-mg TDF tablets (B and E), or 200 mg of FTC plus 300 mg of TDF with a high-fat diet (C and F), respectively. FTC was well-tolerated in all groups. After a single dose, there were no differences in the mean AUC0–∞ values; however, there were significant differences in the mean Tmax values (1.05, 1.40 and 2.10 h for groups A, B and C, respectively; p < 0.05). In the multipledose study, our results were significantly different from published t1/2 values following single-dose FTC. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0031–7012/14/0934–0166$39.50/0 E-Mail [email protected] www.karger.com/pha
Introduction
Although HIV infection and AIDS have been well-controlled by effective treatment regimens in developed countries, the HIV epidemic still poses a major health problem in China, where the incidence of HIV increased by over 25% between 2001 and 2009. AIDS became China’s leading cause of death from infectious diseases for the first time in 2009 [1] while, at the same time, the HIV epidemics in sub-Saharan Africa have been largely under control [2]. Emtricitabine (FTC) is a potent nucleoside reverse transcriptase inhibitor that has been approved for the treatment of AIDS. FTC is rapidly and extensively absorbed following oral administration and its oral bioavailability is about 90% [3, 4]. Recently, pre-exposure chemoprophylaxis (PrEP) of HIV infection has gained increased momentum [5–9]. The US FDA has recommended approval of Truvada® (Gilead Sciences’ pill), the combination of FTC and tenofovir disoproxil fumarate (TDF, Viread®) for PrEP to prevent sexual transmission of HIV. FTC/TDF has been proven effective for PrEP [10]. Although the pharmacokinetics of FTC have been evaluated in both healthy and HIV-infected adults [11– 14], there are no reports from Chinese populations. Since racial differences have been observed in drug metaboProf. Junqing Yang Department of Pharmacology, Chongqing Key Laboratory of Biochemical and Molecular Pharmacology, Chongqing Medical University 1 Medical College Road, Yuzhong District, Chongqing 400016 (PR China) E-Mail junqingyang01 @ 163.com
Downloaded by: UCL 144.82.108.120 - 2/8/2017 11:24:00 AM
Key Words Pharmacokinetics · Emtricitabine · Tenofovir disoproxil fumarate · AIDS · Pre-exposure chemoprophylaxis · Healthy subjects · Chinese population
lism, there is a need to study the FTC pharmacokinetics of a Chinese population. The aim of this study was to evaluate the single- and multiple-dose pharmacokinetics of FTC for future PrEP therapy in China. Subjects, Materials and Methods Study Design This single-centre, randomised, single- and multiple-dose, open-label study was performed at the Clinical Research Centre of the First Affiliated Hospital of Chongqing Medical University (Chongqing, China), from June 2010 to December 2011. The study was conducted in compliance with the Good Clinical Practice Guideline approved by the International Conference on Harmonisation and the ethical principles of the Declaration of Helsinki [15]. The study protocol was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Chongqing Medical University (approval No. 2010010). The study’s aim, procedures and risks were thoroughly explained by clinical investigators to each of the subjects prior to them signing a consent form approved by the ethics committee. Subjects were admitted into the Centre at 8.00 p.m. the day before the study and fasted for 10 h before each drug administration. In the single-dose groups, 30 eligible subjects were randomised into three groups (10 in each group): group A received a single oral dose as a 200-mg FTC capsule; group B received a 200-mg FTC capsule and 300-mg TDF tablet, and group C received the same drugs as group B but served with a high-fat diet (40–50% fat). Drugs were administered with 200 ml of water. In the multipledose groups, another 30 eligible subjects were randomised into three groups (groups D, E and F; 10 in each group) and each group received multiple doses (once daily for 6 days) of the same regimens as group A, B and C in the single-dose study, correspondingly. All other procedures were performed in the same manner as the single-dose groups. The FTC capsules (200 mg) were manufactured and donated by Hebei Medical University Pharmaceutical Factory (Hebei, China), and the TDF tablets (300 mg) were purchased from Gilead Sciences Inc. (Foster City, Calif., USA). Inclusion/Exclusion Criteria Healthy, non-smoking Chinese males aged 20–25 years with a BMI between 19 and 24 were eligible for the study. Inclusion criteria required a healthy status confirmed by medical documentation reporting the results of a physical examination, 12-lead electrocardiography and laboratory tests (serum chemistry, haematology, urinalysis and serology tests). A subject was considered ineligible if he had a history or evidence of neurological, renal, endocrine, cardiovascular, gastrointestinal, hepatic or hematologic abnormality, any acute or chronic disease, or any drug allergy, and any disorder that might interfere with drug absorption, distribution, metabolism or excretion. Eligible subjects were compensated for their participation.
drug dosing and at the same time points as in the single-dose study after the last dosing. All blood samples were immediately centrifuged and plasma samples stored at –20 ° C until analysis [16].
Assessment of Tolerability The tolerability was assessed by monitoring vital signs, blood pressure and heart rate at baseline and at 1, 2, 4 and 6 h after dosing. Physical examinations, 12-lead electrocardiography and clinical laboratory tests were used to determine adverse events, which were collected by spontaneous reporting by the subjects or by investigator inquiries. Analysis of Plasma FTC Plasma concentrations of FTC were assessed using an HPLCUV method [17]. We added 300 μl of plasma sample spiked with internal standard lamivudine and 180 μl of 10% trichloroacetic acid into a 1.5-ml Eppendorf tube. After vortexes, the mixture was centrifuged and the supernatant was neutralised with 1% NaOH and loaded onto preconditioned Bond Elut C-18 solid-phase extraction cartridges. The FTC and lamivudine were eluted with methanol and the eluent was evaporated and reconstituted by mobile phase [20 mM KH2PO4 containing 0.08% triethylamine (pH 3.5, adjusted with H3PO4) and methanol (90:10, v/v)]. Afterwards, aliquots of 100 μl were injected onto the HPLC-UV system. The analyses were conducted at 35 ° C with a detection wavelength of 279 nm. Following FDA guidelines, the method was validated for linearity, recovery, precision, accuracy, stability, matrix effect and selectivity. The calibration curves of FTC were in good linearity within the range of 10–4,000 ng/ml. The lower limit of quantitation of FTC was 7 ng/ml. The average accuracy and intraday precision were 103.30 and
