Mark Castles

Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16 455) and its enantiomers in healthy male volunteers

The pharmacokinetics and dose proportionality of fexofenadine, a new non‐sedating antihistamine, and its enantiomers were characterized after single and multiple‐dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31±8 years) received oral doses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, complete four‐period cross‐over design. Subjects received a single oral dose on day 1, and multiple oral doses every 12 h on day 3 through the morning on day 7. Treatments were separated by a 14‐day washout period. Serial blood and urine samples were collected for up to 48 h following the first and last doses of fexofenadine HCl. Fexofenadine and its R(+) and S(−) enantiomers were analysed in plasma and urine by validated HPLC methods. Fexofenadine pharmacokinetics were linear across the 20–120 mg dose range, but a small disproportionate increase in area under the plasma concentration–time curve (AUC) (<25%) was observed following the 240 mg dose. Single‐dose pharmacokinetics of fexofenadine were predictive of steady‐state pharmacokinetics. Urinary elimination of fexofenadine played a minor role (10%) in the disposition of this drug. A 63:37 steady‐state ratio of R(+) and S(−) fexofenadine was observed in plasma. This ratio was essentially constant across time and dose. R(+) and S(−) fexofenadine were eliminated into urine in equal rates and quantities. All doses of fexofenadine HCl were well tolerated after single and multiple‐dose administration.

Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir

ABSTRACT The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 μCi of [14C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [14C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

In vitro-in vivo correlation for nevirapine extended release tablets.

An in vitro–in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC‐MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin®. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time‐scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles. Copyright

Assessment of Nevirapine Bioavailability From Targeted Sites in the Human Gastrointestinal Tract

This study investigated absorption of nevirapine (NVP) from targeted sites of the gastrointestinal tract using remotely activated capsules and gamma scintigraphy. A total of 24 participants were randomized to receive 50 mg NVP orally as a suspension or via remotely activated capsules for release into the ascending colon. The 24 participants were then rerandomized into parallel groups of n = 8 for drug release into the ileum, jejunum, or descending colon. The mean gastric emptying time of capsules ranged from 0.88 to 3.35 hours. The small intestinal and colon transit time ranged from 4.08 to 7.76 hours and 17.6 to 21.2 hours, respectively, and capsule recovery time ranged from 27.6 to 34.4 hours. The relative bioavailability ratio of NVP in the jejunum was 1.06 (90% confidence interval [CI]: 1.00–1.12) compared to suspension. In the ileum, ascending colon, and descending colon, bioavailability decreased to 0.89 (0.80–0.99), 0.82 (0.71–0.95), and 0.58 (0.22–1.53), respectively. The absorption rate decreased by ∼10‐fold from the jejunum (3.83 h−1) to the descending colon (0.338 h−1), and tmax increased from 2.42 hours (jejunum) to 16.3 hours (descending colon). Overall, NVP is absorbed from all 4 sites of the gastrointestinal tract, and the rate of absorption decreased from the jejunum to the descending colon. Relative bioavailability of NVP was in the order of jejunum > ileum > ascending colon > descending colon.

Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women.

Twenty-four healthy women received 2.4 mg kg-1 dolasetron mesylate (1.8 mg kg-1 dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0.08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0.08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t1/2 = 0.23 h) to MDL 74156 (mean t1/2 = 8.05 and 9.12 h after intravenous and oral administration respectively). MDL 74156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QTc intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men.

Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

ABSTRACT The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.

Concomitant Administration of BILR 355⁄r with Emtricitabine⁄ Tenofovir Disoproxil Fumarate Increases Exposure to Emtricitabine and Tenofovir: A Randomized, Open-Label, Prospective Study

The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355/r) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC/TDF (200/300 mg) once daily (QD) for 7 days and then co-administered with BILR 355/r (150/100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355/r (150/100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administration with BILR 355/r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC(0-24,ss) , C(max,ss) and C(0-12,ss) were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC(0-24,ss) , C(max,ss) and C(24,ss) were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC/TDF resulted in an 18% increase in AUC(0-12,ss) , 14% increase in C(max,ss) and 19% increase in C(12,ss) for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-administration of FTC/TDF with BILR 355/r.

Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects

What is known and Objective:  BILR 355 is a second generation non‐nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti‐HIV‐1 activities and favourable human pharmacokinetic properties after co‐administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter‐mediated pathway. These two drugs are likely to be given together to HIV‐infected patients. The objective of this study was to investigate any steady‐state pharmacokinetic interactions between RTV‐boosted BILR 355 and 3TC/zidovudine (ZDV).

Coadministration with lopinavir and ritonavir decreases exposure to BILR 355, a nonnucleoside reverse transcriptase inhibitor, in healthy volunteers.

The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r‐alone group) were also pooled with group B subjects from 3 similar phase I drug‐drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady‐state area under plasma concentration‐time curve from 0 to 12 hours (AUC0–12, ss) and steady‐state maximum measured plasma concentration over a dosing interval (Cmax, ss) and a 50% decrease in steady‐state plasma concentration 12 hours post last dosing (C12, ss) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355.

Pharmacokinetic characterization of three doses of tipranavir boosted with ritonavir on highly active antiretroviral therapy in treatment-experienced HIV-1 patients.

Abstract Purpose: This study characterized the pharmacokinetic effects, safety, and antiretroviral activity of three different doses of the nonpeptidic protease inhibitor tipranavir, in combination with ritonavir administered twice daily for 28 days, on a number of triple-combination regimens containing a nonnucleoside reverse transcriptase inhibitor (efavirenz or nevirapine) plus two nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, and zidovudine) or a three nucleoside reverse transcriptase inhibitor combination (zidovudine, lamivudine, and abacavir).Methods: The study enrolled 208 HIV-1–positive patients who had been on stable antiretroviral treatment for at least 12 weeks prior to study entry and had an HIV-1 RNA load of δ 20,000 copies/mL. The patients were randomized to receive one of three dose combinations of tipranavir and ritonavir (1250/100 mg, 750/100 mg, and 250/200 mg) in addition to their antiretroviral (ARV) regimen for the next 22 days. The effects of twice-daily tipranavir and ritonavir combinations on the steady-state pharmacokinetics of the antiretrovirals were assessed by comparing pharmacokinetic parameters at baseline and after 3 weeks of coadministration.Results: No clinically relevant changes were observed in the Cmin, Cmax, or AUC parameters for nevirapine, efavirenz, lamivudine, stavudine, or didanosine, when coadministered with tipranavir and ritonavir at the dose combinations studied. All three dose combinations of tipranavir and ritonavir decreased the systemic exposure of abacavir (by 35% to 44%) and zidovudine (by 31% to 42%). Consistent with previous tipranavir studies, gastrointestinal adverse events were those most frequently observed. These reactions tended to be mild, with the majority being of Grade 1, and only 8 being of Grade 3 or 4 in intensity. Virologic response improved from 40.4% of participants at baseline with <50 copies/mL to 67.6% at Day 28 of study following addition of tipranavir and ritonavir.Conclusions: Tipranavir coadministered with ritonavir has been demonstrated to be safe, effective, and pose little potential for clinically meaningful drug interactions when added to the highly active antiretroviral therapy regimens containing nevirapine, efavirenz, lamivudine, stavudine, or didanosine.