Effect of varying degrees of renal impairment on the pharmacokinetics and tolerability of taspoglutide.

AIM: To evaluate single-dose pharmacokinetics and tolerability of taspoglutide in people with varying degrees of renal impairment and matched healthy participants. METHODS: Participants in the present study were people with mild renal impairment (n = 10), moderate impairment (n = 10), severe impairment (n = 9), and a matched healthy control group (n = 10). Participants received a single subcutaneous injection of taspoglutide (10 mg) on day 1. Plasma and urine drug concentration, antibody formation, vital signs, ECGs and routine laboratory variables were measured frequently and adverse events (AEs) were monitored for 9 weeks. RESULTS: Taspoglutide exposure was higher among participants with moderate and severe renal impairment compared with participants with normal renal function. Mean AUClast was 13% and 38% higher in participants with moderate and severe renal impairment, respectively compared with participants with normal renal function. Likewise, mean peak plasma concentration (Cmax ) was 57% and 93% higher in participants with moderate and severe renal function impairment, respectively, compared with participants with normal renal function. Linear regression analyses showed a statistically significant inverse relationship between taspoglutide exposure parameters (AUC and Cmax ) and creatinine clearance. Higher incidences of gastrointestinal (GI) AEs were reported in participants with severe renal impairment. CONCLUSION: Renal impairment altered the pharmacokinetics of taspoglutide. The degree of renal impairment was associated with an increased exposure to taspoglutide and an increased risk of GI AEs.

Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine.

The aim of this study was to evaluate the effect of coadministration of acid-reducing agents on the pharmacokinetic exposure of orally administered epidermal growth factor receptor inhibitor erlotinib, a drug that displays pH-dependent solubility. Two studies were conducted, the first with the proton pump inhibitor omeprazole and the second with the H2-receptor antagonist ranitidine. Twenty-four healthy male and female volunteers were enrolled in each study. Erlotinib was administered as a single oral 150 mg dose on day 1. After the washout a subsequent study period evaluated 150 mg erlotinib administered with the acid-reducing agent. Omeprazole (40 mg once daily) was given on days 11-14, concomitantly with erlotinib on day 15, and for two additional days (days 16-17). In the ranitidine study, on day 13, participants were randomized to either concomitant dosing (treatment B) or staggered administration (treatment C) of erlotinib and ranitidine and crossed over to the other treatment starting on day 27. For treatment B, ranitidine (300 mg once daily) was administered in the morning for 5 days, 2 h before erlotinib. For treatment C, ranitidine was administered as a divided dose (150 mg twice daily) for 5 days, with erlotinib given 10 h after the previous evening dose and 2 h before the next ranitidine morning dose. Plasma samples were obtained for determination of the concentrations of erlotinib and its metabolite OSI-420, following each erlotinib dose. All participants were monitored for safety and tolerability. The geometric mean ratios of AUC0-∞ and Cmax for erlotinib and AUC0-last and Cmax for OSI-420 were substantially decreased when erlotinib was dosed with omeprazole. The estimated mean ratio (90% confidence interval) for erlotinib was 0.54 (0.49-0.59) for AUC0-∞ and 0.39 (0.32-0.48) for Cmax. For OSI-420, the estimated mean ratio was 0.42 (0.37-0.48) for AUC0-last and 0.31 (0.24-0.41) for Cmax. AUC0-∞ and Cmax for erlotinib were substantially decreased by 33 and 54%, respectively, upon coadministration with ranitidine, but the decrease was only 15 and 17% when ranitidine and erlotinib were given staggered. Similar results were observed for the metabolite OSI-420. Erlotinib was generally well-tolerated alone or in combination with omeprazole or ranitidine. Erlotinib pharmacokinetic exposure was substantially reduced upon coadministration with omeprazole and ranitidine, but not when administered with a staggered dosing approach to ranitidine. Therefore, it is recommended that the concomitant use of erlotinib with proton pump inhibitors be avoided. If treatment with an H2-receptor antagonist such as ranitidine is required, erlotinib must be administered 10 h after the H2-receptor antagonist dosing and at least 2 h before the next dose of the H2-receptor antagonist.

Pharmacokinetics and safety of oseltamivir in patients with end-stage renal disease treated with automated peritoneal dialysis.

AIMS: Patients with end-stage renal disease (ESRD) are at increased risk of developing complications associated with influenza infection. Oseltamivir is indicated for influenza treatment in ESRD patients, but the disposition is poorly understood in this patient population. This study aimed to characterize the pharmacokinetics and tolerability of oseltamivir in automated peritoneal dialysis (APD) and construct a pharmacokinetic model to assist with optimized dosing. METHODS: Ten adults with ESRD were prescribed an aggressive APD regimen consisting of three continuous cycler-assisted peritoneal dialysis (CCPD) sessions during the day and two continuous ambulatory (CAPD) sessions overnight. Oseltamivir was administered as a single 75 mg dose, immediately before APD treatment. RESULTS: Oseltamivir was rapidly eliminated via first-pass metabolism, with most of the dose (Fraction metabolized = 0.964) reaching the circulation as the active metabolite, oseltamivir carboxylate. This metabolite was cleared slowly and was quantifiable throughout the sampling interval. The disposition of oseltamivir and oseltamivir carboxylate was described by a two- and a one-compartment model, respectively. Metabolite clearance by CCPD [0.32 l h(-1) (70 kg)(-1) ] was 1.9-fold faster than via CAPD [0.17 l h(-1) (70 kg)(-1) ], with renal elimination being dominant in patients with residual urine production. Model simulations showed that a single 75 mg dose attained target exposures in patients with negligible or low urine clearance. However, higher doses are recommended for further investigation in patients with high residual renal function. In all patients, oseltamivir was well tolerated. CONCLUSIONS: In APD patients with anuria or low residual renal elimination, a single 75 mg dose of oseltamivir produced exposures at the upper end of the safety margin.

Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment.

This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40-200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20-1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL M ) and exposure. CL M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC Cmin coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups.

A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail.

PURPOSE: The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C. METHODS: A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated. RESULTS: Danoprevir/r and placebo/r significantly increased midazolam area under the time-concentration curve (AUC0-∞) and reduced the midazolam metabolic ratio while S-warfarin AUC0-∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC0-∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC0-∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar. CONCLUSIONS: Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.

Intravenous tocilizumab for the treatment of giant cell arteritis: a phase Ib dose-ranging pharmacokinetic bridging study.

BACKGROUND: Subcutaneous tocilizumab (TCZ SC) is approved globally for giant cell arteritis (GCA). This phase Ib study investigated the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of intravenous (IV) TCZ 6 and 7 mg/kg in patients with GCA. This study explored an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA). METHODS: Patients with GCA who had received ≥ 5 doses of TCZ IV 8 mg/kg Q4W and achieved remission were enrolled. Patients received 5 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, 5 doses of 6 mg/kg Q4W in period 2. Pharmacokinetic endpoints were maximum concentration (Cmax), minimum concentration (Ctrough), area under the curve over a dosing interval (AUCτ), and mean concentration (Cmean) of TCZ after the last dose of each period. Other endpoints included pharmacodynamic markers, safety, and exploratory efficacy. RESULTS: In 24 patients, the median (range) age was 65.5 (57-90) years, and 62.5% were female. TCZ exposures (Cmax and AUCτ) were 11.2% and 20.0% lower at the 6- than 7-mg/kg dose. The mean interleukin 6 (IL-6) serum concentrations were elevated at baseline and remained elevated, with slightly higher concentrations in period 1 than in period 2. The mean serum soluble IL-6 receptor concentrations were elevated at baseline and comparable between the 2 doses at steady state. C-reactive protein levels and most erythrocyte sedimentation rates were within normal ranges throughout the study. Overall, 22 patients (91.7%) had ≥ 1 adverse event, and 4 (16.7%) had a serious adverse event. No patients experienced a GCA flare, and all remained in remission throughout the study. CONCLUSIONS: Both doses of TCZ IV Q4W were generally well tolerated in patients with GCA. The Cmax and Cmean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those in patients with RA treated with 8 mg/kg IV Q4W, and Ctrough was within the range observed in patients with GCA treated with SC dosing every week or every 2 weeks. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03923738.

Assessment of Drug-Drug Interactions between Taspoglutide, a Glucagon-Like Peptide-1 Agonist, and Drugs Commonly Used in Type 2 Diabetes Mellitus: Results of Five Phase I Trials.

BACKGROUND AND OBJECTIVE: Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects. METHODS: Five clinical pharmacology studies evaluated the potential drug-drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration-time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive. RESULTS: Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by - 26% and - 58% for the area under the plasma concentration-time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin ß-hydroxy acid (+ 74% and + 23% for area under the plasma concentration-time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration-time curve were within the 0.7-1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent. CONCLUSION: Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration.

Phase I Trial of Anti-Vascular Endothelial Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular Age-Related Macular Degeneration.

PURPOSE: RG7716 is a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and another key angiogenic factor, angiopoietin 2. A phase I study of intravitreal RG7716 was conducted to evaluate single-dose and multiple-dose safety in patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, single and multiple ascending-dose study. PARTICIPANTS: Twenty-four patients diagnosed with neovascular AMD with best-corrected visual acuity (BCVA) of 20/40 to 20/400 (Snellen equivalent) and refractory subfoveal choroidal neovascularization defined as leakage on fluorescein angiography or fluid on spectral-domain optical coherence tomography despite 3 or more intravitreal anti-VEGF treatments in the preceding 6 months. METHODS: Single intravitreal doses of 0.5 mg, 1.5 mg, 3 mg, and 6 mg RG7716 were administered in stepwise dose-escalation groups, each with 3 patients. In the multiple-dose phase, 6 patients were enrolled and received 3 treatments each of 3 mg and 6 mg RG7716. MAIN OUTCOME MEASURES: Safety and tolerability, changes in baseline BCVA, and central subfield thickness (CST). RESULTS: There were no dose-limiting toxicities in either the single-dose or multiple-dose group. Treatment-emergent ocular adverse events were mild. There was a single withdrawal and 1 serious adverse event, both deemed to be unrelated to the study drug by principal investigators. In the combined single-dose groups and in the 6-mg multiple-dose group, BCVA increased from baseline to 28 days after the last dose administration by a median of 7 letters (range, 0-18 letters; n = 11) and 7.5 letters (range, 3-18 letters; n = 6), respectively. The corresponding median reduction from baseline in CST were 42 µm (range, -101 to 10 µm; n = 11) and -117 µm (range, -252 to -7 µm; n = 6), respectively. After multiple 3-mg RG7716 doses, no changes were observed in either BCVA (median, -0.5 letters; range, -9 to 8 letters; n = 6) or CST (median, -9 µm; range, -188 to -1 µm; n = 6). CONCLUSIONS: RG7716 was well tolerated and exhibited an overall favorable safety profile, with evidence of improvements in BCVA and anatomic parameters. These data support further evaluation of RG7716 in phase II trials.

Effect of a modified saquinavir/ritonavir dosing regimen with lower dose lead-in phase on QTc interval, pharmacokinetics, antiviral activity and safety in treatment-naïve HIV-1-infected patients.

BACKGROUND: Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations. OBJECTIVE: To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients. METHODS: Twenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1-7 and 1000/100 mg BID on days 8-14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia's formula (∆QTcFdense) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days. RESULTS: The mean maximum ∆QTcFdense was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcFdense ≥30 ms (on day 10); the highest mean ∆QTcFdense was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated. CONCLUSION: Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment.