title: Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers.
abstract: A clinical study was conducted to assess the ability of a microdose (100 μg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 μg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 μg iv (14)C-doses were given alone and with an oral non-labelled therapeutic dose, excellent accord between the PK parameters was observed indicating that the disposition kinetics of the drugs tested were unaffected by the presence of therapeutic concentrations. This observation implies that any deviation from linearity following the oral therapeutic doses occurs during the absorption process.
authors.affiliation: Xceleron Ltd., The Biocentre, Innovation Way, York YO10 5NY, UK. graham.lappin@xceleron.com
authors.forename: Graham
authors.initials: G
authors.lastname: Lappin
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shishikura
authors.forename: Roeline
authors.initials: R
authors.lastname: Jochemsen
authors.forename: Richard John
authors.initials: RJ
authors.lastname: Weaver
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gesson
authors.forename: J
authors.initials: J
authors.lastname: Brian Houston
authors.forename: Berend
authors.initials: B
authors.lastname: Oosterhuis
authors.forename: Ole J
authors.initials: OJ
authors.lastname: Bjerrum
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grynkiewicz
authors.forename: Jane
authors.initials: J
authors.lastname: Alder
authors.forename: Malcolm
authors.initials: M
authors.lastname: Rowland
authors.forename: Colin
authors.initials: C
authors.lastname: Garner
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D017291:Clarithromycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D010634:Phenobarbital / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011405:Propafenone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018170:Sumatriptan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D002250:Carbon Radioisotopes; D000082:Acetaminophen; D011405:Propafenone; D018170:Sumatriptan; D017291:Clarithromycin; D010634:Phenobarbital