Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs

Lappin, Graham; Kuhnz, W.; Jochemsen, R.; Kneer, Johannes; Chaudhary, Archana; Oosterhuis, B.; Drijfhout, W. J.; Rowland, Malcolm; Garner, R. Colin

doi:10.1016/j.clpt.2006.05.008

Cited by 224 publications

(249 citation statements)

References 26 publications

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“…dose at the T max of the oral dose determines i.v. pharmacokinetics at therapeutically relevant concentrations of the compound, thereby addressing concerns regarding pharmacokinetic linearity of the microdose, and improves precision of the bioavailability estimate due to the lack of interoccasion variability 8, 9, 10, 11…”

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confidence: 99%

“…The microtracer approach, where doses are typically 1/100th to 1/1,000th of the therapeutic dose (or ≤100 μg), and, in cases in which radioisotopes are administered, radioactivity is <1,000 nCi, provides several advantages over traditional methods 8, 9, 10, 11. If the radioactive dose administered is very low (<1,000 nCi), subjects are exposed to extremely low amounts of radiation; therefore, supporting data from dosimetry studies in animals are not required 8.…”

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confidence: 99%

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Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Raje

Callegari

Sahasrabudhe

et al. 2018

Clinical Translational Sci

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Ertugliflozin, a sodium glucose cotransporter‐2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two‐period study design with 14C microtracer dosing in each period was used to determine absolute oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin. Eight healthy adult men received 100‐μg i.v. 14C‐ertugliflozin (400 nCi) dose 1 h after a 15‐mg oral unlabeled ertugliflozin dose (period 1), followed by 100 μg 14C‐ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concentrations were determined using high‐performance liquid‐chromatography tandem mass spectrometry (HPLC‐MS/MS). 14C‐ertugliflozin plasma concentrations were determined using HPLC‐accelerator mass spectrometry (AMS) and 14C urine concentrations were determined using AMS. F ((area under the curve (AUC)p.o./14C‐AUCi.v.)*(14C‐Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C‐Dosei.v./14C‐Dosep.o.)) were estimated. Estimates of F and Fa were 105% and 111%, respectively. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.

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confidence: 99%

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confidence: 99%

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Raje

Callegari

Sahasrabudhe

et al. 2018

Clinical Translational Sci

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“…Because these doses are far below the no observed adverse effect level (NOAEL) it is an attractive approach to assess a drug's propensity to exert pharmacokinetic drug interactions in early drug development and also in vulnerable populations. To be useful and predictive, it needs systematic validation to show dose linearity [13].…”

Section: Introductionmentioning

confidence: 99%

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Hohmann

Kocheise

Carls

et al. 2015

Brit J Clinical Pharma

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AIMWe aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. METHODSIn an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. RESULTS Dose CONCLUSIONThe pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Midazolam pharmacokinetics of oral doses are linear over a 30 000-fold range.• An oral microdose of midazolam is suitable to measure total CYP3A activity.• CYP3A inhibition with strong inhibitors can be evaluated with a microdose in healthy volunteers and patients. WHAT THIS STUDY ADDS• The pharmacokinetics of intravenous midazolam microdoses are linear to milligram doses.• The bioavailability and metabolic clearance of midazolam is similar after administration of microdoses and milligram doses.• Midazolam microdoses are a suitable tool to assess both systemic and pre-systemic CYP3A activity.

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“…As part of a wider strategy to address the current high rate of attrition for new chemical entities that proceed to clinical development, both the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) have issued guidance documents to support the use of exploratory (Phase 0) studies in the early evaluation of the PK and PD properties of such compounds in humans [25,26,28].In this regard, an emerging literature reveals how microdose studies using highly sensitive analytical methods, namely LC/MS/MS and accelerator MS (AMS) can be used to extrapolate the PK profile of compounds and metabolites (assuming linearity of exposure with dose) to higher clinically relevant doses [22,27,[29][30][31]. However, few microdose investigations have been reported specifically in the context of drug development and their value to the overall process has yet to be fully established [20,22,23].…”

Section: Discussionmentioning

confidence: 99%

“…A second consideration is that there may be a lack of agreement between the PK profile seen following microdose administration and that seen at higher doses, which may reflect non-linearity in absorption, distribution, metabolism and/or excretion over the dose range [20,22]. To date, a formal comparison of microdose with therapeutic dose PK data has only been undertaken in the clinical setting for a few established drugs of limited chemical diversity [27,29,49], so the predictive value of the methodology has yet to be fully defined. It also remains to be seen whether the scope of application of microdose data, when combined with human in vitro data, might be usefully broadened to update the assumptions underpinning physiologically-based PK (PBPK) models and thereby enhancing their predictive value [50].…”

Section: Figurementioning

confidence: 99%

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost‐efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies.• The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub‐pharmacological doses up to the therapeutic dose range.• Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated.WHAT THIS STUDY ADDS• The present study describes the elective application of a human microdose study with a novel EP1 receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile.• Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision‐making.AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography‐tandem mass spectrometry method following solid phase extraction.RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady‐state volume of distribution (Vss) and terminal elimination half‐life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre‐clinical species (rat, dog and monkey).CONCLUSION For drug development programmes characterized by inconsistencies between pre‐clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

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Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs

Abstract: Overall, when used appropriately, microdosing offers the potential to aid in early drug candidate selection.

Cited by 224 publications

References 26 publications

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

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