Confidence Intervals For AUC0 Research Articles

Bioequivalence Evaluation in Healthy Volunteers: New Generic Formulations of Sitagliptin and Sitagliptin-Metformin Fixed-Dose Combination Compared with the Originator Products.

Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850mg, 50/1000mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUC0-t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0-t and Cmax were within BE acceptance range of 80.00-125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100mg), 26/25 (FDC 50/850mg), and 26/24 (FDC 50/1000mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0-t and Cmax were 95.83-100.37% and 91.85-109.56% (sitagliptin 100mg); 100.84-103.69% and 93.44-105.10% (FDC 50/850mg), and 101.26-105.20% and 98.71-112.89% (FDC 50/1000mg); respective values for metformin were 94.23-101.89% and 91.66-99.38% (FDC 50/850mg) and 98.45-104.89% and 96.79-105.62% (FDC 50/1000mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. The new generic tablet formulations of sitagliptin 100mg and the FDCs sitagliptin/metformin 50/850mg and 50/1000mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).

Abstract CT132: Effect of gastric acid reduction and strong CYP3A induction/inhibition on the pharmacokinetics of ripretinib, a switch control tyrosine kinase inhibitor

Abstract Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with 3 or more kinase inhibitors, including imatinib. In a phase 1 study in patients with advanced malignancies, the maximum tolerated dose was not reached at doses up to 200 mg twice daily (BID). Dose escalation to ripretinib 150 mg BID was offered in the phase 1 and phase 3 clinical studies after radiologic disease progression at 150 mg once daily (QD) and was well tolerated with a similar safety profile as seen with 150 mg QD (approved dose regimen). Ripretinib solubility is pH dependent and ripretinib and its active metabolite (DP-5439) are cleared via CYP3A4/5; thus, drug-drug interactions (DDIs) with acid-reducing agents and strong CYP3A inhibitors/inducers were assessed. Here, we report the effects of pantoprazole (proton pump inhibitor), itraconazole (strong CYP3A inhibitor) and rifampin (strong CYP3A inducer) on the pharmacokinetics (PK) of ripretinib and DP-5439. Ripretinib PK is generally dose proportional within 50-150 mg. For each interaction, single oral doses of ripretinib (either 50 mg for pantoprazole and itraconazole or 100 mg for rifampin) were given before and concurrently with multiple doses of each perpetrator agent to healthy volunteers: pantoprazole 40 mg QD x 7 days (n = 25), itraconazole 200 mg QD x 10 days (n = 20), and rifampin 600 mg QD x 14 days (n = 24). Serial blood samples were collected over 4-7 days before and after each perpetrator drug; plasma concentrations of ripretinib and DP-5439 were determined by validated LC-MS/MS. The geometric least-squares mean (GLSM) ratios of PK parameters (i.e., AUC0-∞ and Cmax) and corresponding 90% confidence intervals (CIs) were calculated. No DDI was observed between ripretinib and pantoprazole. The ratios of GLSM and 90% CIs for AUC0-∞ and Cmax were within the bioequivalence 80%−125% range for ripretinib with pantoprazole vs ripretinib alone. Concomitant itraconazole increased exposure to ripretinib and DP-5439; GLSM ratios for ripretinib AUC0-∞ and Cmax were 199% and 136%, respectively, and similar ratios were noted for DP-5439. Exposure to ripretinib and DP-5439 based on AUC0-∞ decreased with rifampin coadministration. GLSM ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%, respectively, for ripretinib with rifampin vs ripretinib alone, and were 43% and 137% for DP-5439. No dose adjustments are required when ripretinib is coadministered with either gastric acid reducers or strong CYP3A inhibitors, based on the magnitude of DDI PK effects in healthy volunteers, and the safety profile of ripretinib observed in patients and healthy volunteers. However, as decreased exposure may reduce the antitumor activity of ripretinib, concomitant use of strong CYP3A inducers with ripretinib should be avoided. Citation Format: Xiaoyan Li, Mark J. Shelton, Julie Meade, Cherie Taglienti, Constance Barysauskas, Rodrigo Ruiz-Soto, Jing Wang. Effect of gastric acid reduction and strong CYP3A induction/inhibition on the pharmacokinetics of ripretinib, a switch control tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT132.

A bioequivalence study of two telmisartan 80 mg tablets in healthy Indonesian subjects: an open label, three-way, three-period, partial replicate crossover study

Telmisartan is highly variable drug indicated for treatment of hypertension. This study aimed to compare the bioavailability of two 80 mg telmisartan tablets in healthy Indonesian subjects. A randomized, open-label, single-dose, three-sequence, three-way, reference-formulation-replicated crossover study was conducted under fasting period with two-week washout period. In this study, 31 Indonesian subjects were enrolled and 28 subjects were completed the study. Serial blood samples were collected up to 72 h following drug administration. Plasma concentrations of telmisartan were determined using high-performance liquid chromatography method with fluorescence detector. The pharmacokinetic parameters of AUC0– t , AUC0–∞, and C max were assessed for bioequivalence. Bioequivalence acceptance was based on predefined criteria of 90% confidence interval (CI) of 80.00–125.00% for AUC parameters and reference-scaled-average bioequivalence of 71.73–139.42% for C max. The 90% CI for AUC0– t , AUC0–∞, and C max was 96.11–107.25%, 93.06–104.36%, and 94.23–127.01%, respectively. These results indicated that the two formulations of telmisartan were bioequivalent.

A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition

BackgroundParacetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia.MethodThis is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (− 15 °C to − 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00–125.00%.ResultsThere were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92–111.27%), AUC0-∞ (96.94–108.08%) and Cmax (100.11–112.50%) for orphenadrine (n = 25); and AUC0-t (94.29–101.83%), AUC0-∞ (94.77–101.68%) and Cmax (87.12–101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00–125.00%.ConclusionThe test preparation is bioequivalent to the reference preparation and can be used interchangeably.Trial registrationNMRR- 17-1266-36,001; registered and approved on 12 September 2017.

Evaluation of the Potential for Drug Interactions With Patiromer in Healthy Volunteers.

Introduction:Patiromer is a potassium-binding polymer that is not systemically absorbed; however, it may bind coadministered oral drugs in the gastrointestinal tract, potentially reducing their absorption.Methods:Twelve randomized, open-label, 3-period, 3-sequence crossover studies were conducted in healthy volunteers to evaluate the effect of patiromer (perpetrator drug) on absorption and single-dose pharmacokinetics (PK) of drugs (victims) that might be commonly used with patiromer. Subjects received victim drug alone, victim drug administered together with patiromer 25.2 g (highest approved dose), and victim drug administered 3 hours before patiromer 25.2 g. The primary PK endpoints were area under the curve (AUC), extrapolated to infinity (AUC0-∞), and maximum concentration (C max). Results were reported as 90% confidence intervals (CIs) about the geometric mean AUC0-∞ and C max ratios with prespecified equivalence limits of 80% to 125%.Results:Overall, 370 subjects were enrolled, with 365 receiving ≥1 dose of patiromer; 351 subjects completed the studies and all required treatments. When coadministered with patiromer, the 90% CIs for AUC0-∞ remained within 80% to 125% for 9 drugs (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). The AUC0-∞ point estimate ratios for levothyroxine and metformin with patiromer coadministration were ≥80%, with the lower bounds of the 90% CIs at 76.8% and 72.8%, respectively. For ciprofloxacin, the point estimate for AUC0-∞ was 71.5% (90% CI: 65.3-78.4). For 8 of 12 drugs, point estimates for C max were ≥80% with patiromer coadministration; for ciprofloxacin, clopidogrel, metformin, and metoprolol, the point estimates were <80%. When patiromer was administered 3 hours after each victim drug, the 90% CIs for AUC0-∞ and C max for each drug were within the prespecified 80% to 125% limits.Conclusion:For 9 of the 12 drugs coadministered with patiromer, there were no clinically significant drug–drug interactions. For 3 drugs (ciprofloxacin, levothyroxine, and metformin), a 3-hour separation between patiromer and their administration resulted in no clinically significant drug–drug interactions.

The Effects of Multiple Doses of Rolofylline on the Single-Dose Pharmacokinetics of Midazolam in Healthy Subjects

Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute decompensated heart failure and renal function impairment. This was a phase I, randomized, open-label, 2-period, fixed-sequence study in 19 healthy adult volunteers to examine the effect of multiple intravenous rolofylline doses on the single-dose pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. In period 1, subjects received a single oral dose of midazolam 7.5 mg on day 1. In period 2, subjects received 30 mg, 4-hour infusions of rolofylline (intended clinical dose and duration) once daily for 4 consecutive days; midazolam 7.5 mg was coadministered on day 4. The geometric mean ratios and 90% confidence intervals for AUC0-infinity and Cmax of midazolam in the presence/absence of rolofylline were 1.20 (1.12-1.29) and 1.17 (1.03-1.32), respectively. The apparent terminal half-life (t1/2) for midazolam was similar in the presence/absence of rolofylline (4.31 and 4.27 hours, respectively). The geometric mean ratios (90% confidence intervals) for AUC0-infinity and Cmax of 1'-hydroxymidazolam in the presence/absence of rolofylline were 1.04 (0.96-1.13) and 0.98 (0.84-1.14), respectively. The t1/2 for 1'-hydroxymidazolam was slightly higher in the presence relative to absence of rolofylline (4.24 and 3.17 hours, respectively). Multiple doses of intravenous rolofylline 30 mg for 4 days were generally well tolerated and did not result in clinically important inhibition of CYP3A4 as indicated by little or no change in the pharmacokinetics of midazolam.

Lack of a Clinically Important Effect of Moderate Hepatic Insufficiency and Severe Renal Insufficiency on Raltegravir Pharmacokinetics

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.73 m(2)) on the pharmacokinetics of raltegravir. Study I evaluated the pharmacokinetics of 400 mg raltegravir in eight patients with moderate hepatic insufficiency and eight healthy, matched control subjects. Study II evaluated the pharmacokinetics of 400 mg raltegravir in 10 patients with severe renal insufficiency and 10 healthy, matched control subjects. All participants received a single 400-mg dose of raltegravir in the fasted state. In study I, the geometric mean ratios (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% confidence intervals (CIs) for the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)), the maximum concentration of drug in plasma (C(max)), and the concentration at 12 h (C(12)) were 0.86 (90% CI, 0.41, 1.77), 0.63 (90% CI, 0.23, 1.70), and 1.26 (90% CI, 0.65, 2.43), respectively. In study II, the GMRs (mean value for the group with renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC(0-infinity), C(max), and C(12) were 0.85 (90% CI, 0.49, 1.49), 0.68 (90% CI, 0.35, 1.32), and 1.28 (90% CI, 0.79, 2.06), respectively. Raltegravir was generally well tolerated by patients with moderate hepatic or severe renal insufficiency, and there was no clinically important effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of raltegravir. No adjustment in the dose of raltegravir is required for patients with mild or moderate hepatic or renal insufficiency.