Clinical pharmacokinetics of procaterol: Dose proportionality after administration of single oral doses

AbstractObjectives: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20,40, and 60 mg.Methods: Study A, an open-label single-period study, and Study B, a randomized, open-label, three threeway crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20,40, and 60 mg separated by 7-14-day washout periods.Findings: Plasma dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of D-amphetamine to L-amphetamine was observed for AUC0-∞ and Cmax. Tmax was 4.2 and 4.3 hours for D-amphetamine to Lamphetamine, respectively. In Study B, for D- and Lamphetamine, statistically significant differences were observed for AUC0-t, AVC0-∞, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5–5.3 hours) with all given MAS XR doses.Conclusion: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of D-amphetamine to L-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

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Clinical Pharmacokinetics of Daprodustat: Results of an Absorption, Distribution, and Excretion Study With Intravenous Microtracer and Concomitant Oral Doses for Bioavailability Determination

Clinical Pharmacology in Drug Development ◽

10.1002/cpdd.1029 ◽

2021 ◽

Author(s):

Kelly M. Mahar ◽

Stephen Caltabiano ◽

Susan Andrews ◽

Bandi Ramanjineyulu ◽

Liangfu Chen ◽

...

Keyword(s):

Clinical Pharmacokinetics ◽

Excretion Study ◽

Oral Doses

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Oblimersen can be administered by subcutaneous (SC) and brief intravenous (IV) infusion: Clinical pharmacokinetics and pharmacodynamics (PK/PD) in patients with advanced cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14083 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14083-14083

Author(s):

C. Lin ◽

K. Papadopoulos ◽

A. Patnaik ◽

K. Sankhala ◽

C. H. Takimoto ◽

...

Keyword(s):

Compartmental Analysis ◽

Dose Proportionality ◽

Continuous Intravenous Infusion ◽

Pharmacokinetics And Pharmacodynamics ◽

Dose Escalation Study ◽

Peripheral Blood Mononuclear ◽

Clinical Pharmacokinetics ◽

Protein Levels ◽

Dosing Regimens ◽

Dose Ranging

14083 Background: Oblimersen (OBL) is a phosphorothioate oligodeoxynucleotide that decreases Bcl-2 protein levels. OBL has been administered by continuous intravenous infusion (CIVI) in most clinical studies. However, recent preclinical data suggest that equivalent or superior antitumor efficacy can be achieved with intermittent administration. We conducted a dose-ranging PK/PD study of OBL given by bolus SC injection and brief IV infusion to evaluate the feasibility of intermittent dosing. Methods: In this within-subject dose-escalation study, OBL was administered subcutaneously (SC) at doses of 75, 150 and 225 mg. In part II of the study, OBL was administered by 2-hr IV infusion beginning at 150 mg on day 1, by single-dose SC injection on day 8, and 2-hr IV daily x 5 consecutive days. Pharmacokinetics were assessed by non-compartmental analysis. Pharmacodynamic measurements of Bcl-2 levels in peripheral blood mononuclear (PBM) cells were made using Western blot analysis. Results: OBL absorption after SC administration was rapid with a Tmax of ∼2 hours. Mean Cmax values were 0.76, 1.70 and 3.10 μg/ml for the 75, 150 and 225 mg SC doses, respectively. Mean AUC0- inf values were 7.78, 15.36 and 25.57 hr*μg/mL. Plots of dose-normalized Cmax and AUC vs. dose showed slopes close to zero, indicating approximate dose proportionality. AUC0–24 exposure with the 225 mg SC dose was similar to previously established 24-hr steady-state AUCs after 3 mg/kg CIVI. SC injection was associated with an inflammatory erythematous grade 1 rash at the injection site that resolved within 7 days. The 150 mg 2-hr IV infusion x 1 or daily x 5 has been well-tolerated. Conclusions: OBL exposure from a single SC injection is similar to a 24-hr 3 mg/kg CIVI, and the 2-hr IV infusion is currently being evaluated. Both schedules appear to be well- tolerated, may reduce requirements for CIVI, and could be incorporated into intermittent dosing regimens. No significant financial relationships to disclose.

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Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-014-2398-8 ◽

2014 ◽

Vol 73 (4) ◽

pp. 721-727 ◽

Cited By ~ 11

Author(s):

Dongyang Liu ◽

Ji Jiang ◽

Li Zhang ◽

Fenlai Tan ◽

Yingxiang Wang ◽

...

Keyword(s):

Healthy Subjects ◽

Food Effect ◽

Drug Evaluation ◽

Dose Proportionality ◽

Cancer Drug ◽

Clinical Pharmacokinetics ◽

Anti Cancer

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Therapeutic Doses of Eltrombopag do not Inhibit Hepatic BCRP in Healthy Volunteers: Intravenous Ceftriaxone as a Model

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps29856 ◽

2018 ◽

Vol 21 ◽

pp. 236-246 ◽

Cited By ~ 5

Author(s):

Daniel Valente Neves ◽

Carolina Pinto Vieira ◽

Adriana Rocha ◽

Vera Lucia Lanchote

Keyword(s):

Human Subjects ◽

Total Concentration ◽

Cancer Resistance ◽

Clinical Pharmacokinetics ◽

Pharmacokinetic Drug Interaction ◽

Coefficients Of Variation ◽

Assay Precision ◽

Therapeutic Doses ◽

Oral Doses

PURPOSE: Ceftriaxone elimination occurs through breast cancer resistance transporter (BCRP) and multidrug resistance-associated protein 2 (MRP-2) which are expressed on the canalicular membrane of hepatocytes. Eltrombopag, a thrombopoetin receptor agonist used in the treatment of immune thrombocytopenic purpura, is reported in in vitro studies as an inhibitor of intestinal BCRP but not an inhibitor of hepatic BCRP. Thus, the present study evaluates the effect of therapeutic doses of eltrombopag on the clinical pharmacokinetics of intravenous ceftriaxone. METHODS: Healthy adult (n=12) were treated with oral doses of eltrombopag (0, 25 or 50 mg) 28 and 4 h prior to intravenous ceftriaxone administration (1g). Serial blood samples were collected up to 48 h after ceftriaxone administration and plasma samples were analysed by LC-MS/MS using 50 μL aliquots (total concentration) and 100 μL (unbound concentration). RESULTS: A method to analyze total and unbound ceftriaxone in plasma using LC-MS/MS was developed and validated with linearity from 1 to 200 μg/mL. Both methods are sensitive, precise and accurate with coefficients of variation less than 15% in the study of inter- and intra-assay precision and accuracy. Ceftriaxone pharmacokinetics in healthy adults were described using a bicompartmental model, with a mean clearance of 0.96 L/h (CI95% 0.71-1.20) and AUC0-∞of 1106 mg.h/mL (CI95% 811-1400) for volunteers that received only ceftriaxone; clearance of 0.95 L/h (CI95% 0.77-1.13) and AUC0-∞ of 1083 mg.h/mL (CI95% 876-1290) for volunteers that received ceftriaxone plus 25 mg of eltrombopag and clearance of 0.96 L/h (CI95% 0.74-1.19) and AUC0-∞ of 1072 mg.h/mL (CI95% 872-1273) for volunteers that received ceftriaxone plus 50 mg of eltrombopag. CONCLUSIONS: The results do not support the existence of a clinical pharmacokinetic drug interaction involving hepatic BCRP in human subjects receiving intravenous ceftriaxone and oral eltrombopag. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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