Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers

Lappin, Graham; Shishikura, Yoko; Jochemsen, R.; Weaver, Richard J.; Gesson, Charlotte; Houston, J. Brian; Oosterhuis, B.; Bjerrum, Ole J.; Grynkiewicz, Grzegorz; Alder, Jane; Rowland, Malcolm; Garner, Colin

doi:10.1016/j.ejps.2011.04.009

Cited by 52 publications

(55 citation statements)

References 64 publications

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“…Published values of acetaminophen t 1/2 [2.6 h (Critchley et al 2005)] obtained at therapeutic dosages seem to be smaller than the value obtained in this study (6.0 h). Our data are, however, very close (6.0 vs 5.8 h) to the value reported after dosing of 0.1 mg acetaminophen using a microdose cocktail (Lappin et al 2011). Other acetaminophen PK parameters and acetaminophen AUC to glucuronide metabolite AUC ratio were close to the literature values (see Tables 2, 3).…”

Section: Discussionsupporting

confidence: 90%

“…For metabolites (which were not administered to volunteers), given doses are the dose of the corresponding parent probe b Conversion from L/h/kg into L/h for a mean weight of 70 kg c Conversion from CLiv estimation into CL/F using F = 88 %(Lappin et al 2011) d Estimated using the formula CL/F = dose/AUC e Conversion from CLiv estimation into CL/F using F = 60 %(Blickle 2006) …”

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confidence: 99%

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Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

Lenuzza

Duval

Nicolas

et al. 2014

Eur J Drug Metab Pharmacokinet

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This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

Lenuzza

Duval

Nicolas

et al. 2014

Eur J Drug Metab Pharmacokinet

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“…A recent review indicated that 27 of 35 (77 %) published cases comparing microdose and therapeutic dose pharmacokinetics displayed dose proportionality [12]. Importantly, these published cases include compounds that were specifically selected to address concerns about saturable processes that were raised a priori [2,[33][34][35][36]. It was suggested that such cases may be foreseeable by integrating the available preclinical data, but this had not yet been formally evaluated.…”

Section: Discussionmentioning

confidence: 95%

“…From the published cases comparing microdose and therapeutic dose pharmacokinetics [2,[33][34][35][36], we addressed ten cases for which concerns were expressed a priori about processes that might saturate at higher doses ( Table 1). The K m values for the processes of concern, established with in vitro tests, were collected from scientific literature ( Table 1).…”

Section: Evaluation Of the Decision Tree With Selected Casesmentioning

confidence: 99%

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

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Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

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“…In other words, a discrepancy may arise between the pharmacokinetic profiles of new drug candidates following the administration of a trace dose and those following the application of a therapeutic dose. This predictive failure may be due to the nonlinearity of the pharmacokinetic profiles following trace and therapeutic doses and/or to methodological errors committed in microdosing studies (Lappin et al, 2011). The questionable reliability of predictions based on microdosing study results poses a great obstacle to the validity and usefulness of this innovative technological application.…”

Section: Potential Lack Of Predictive Ability Of Microdosing Study Rementioning

confidence: 99%

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

Bae

Shon

2011

Arch. Pharm. Res.

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Innovative attempts have been made to overcome nonproductivity and high expenditure in the clinical stages of new drug development. Microdosing studies using subpharmacological doses provide early insight into the body's disposition toward candidate compounds, and are innovative exploratory trials that can promote productivity in drug development. Highly sensitive analytical technology is crucial in microdosing studies that employ qualitative and quantitative assays of target materials in humans. Accelerator mass spectrometry (AMS) has facilitated the adoption of a human microdosing study in the early phase of clinical drug development. Results derived from AMS microdosing studies using labeled compounds can provide various types of information for candidate selection, including pharmacokinetic characteristics and metabolic profiles of candidate compounds. The applicability of microdosing studies is currently expanding into absolute bioavailability and mass balance studies. Although it remains uncertain whether microdosing adequately predicts the pharmacokinetics of therapeutic doses, further development of microdosing studies using AMS may benefit the field of new drug development and could pose a new challenge to researchers. The use of advanced technology in candidate selection will contribute to improved productivity and competitiveness in pharmaceutical research and development. The introduction of microdosing studies using AMS in Korea will present a newly applicable method for innovative clinical trials and contribute to development potential in global competition.

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Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers

Cited by 52 publications

References 64 publications

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

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