Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Vlaming, Mlh; Duijn, Esther van; Dillingh,; Brands, Ruud; Windhorst, Albert D.; Hendrikse, N. Harry; Bosgra, Sieto; Burggraaf, Jacobus; Koning, MC de; Fidder, A.; Mocking, Jaj; Sandman, H.; Ligt, Raf de; Fabriek, BO; Pasman, W. J.; Seinen, Willem; Alves, Tânia Maria de Almeida; Carrondo, Manuel J.T.; Peixoto, Cristina; Peeters, Pam; Vaes, Whj

doi:10.1002/cpt.131

Cited by 22 publications

(32 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The published microdosing studies contain the well-known but possibly exceptional case of warfarin, the pharmacokinetics of which are believed to be driven by binding to its therapeutic target [68]. This target-mediated disposition is more common in certain-but not all [73]-classes of biologics, but is not often associated with small molecules. To get an impression of the occurrence of low-dose saturation phenomena, we studied the abstracts of ascendingdose studies indexed in PubMed over the last decade.…”

Section: Discussionmentioning

confidence: 96%

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

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 96%

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

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

View full text Add to dashboard Cite

show abstract

“…This approach would also potentially allow the conduct of ADME type investigations in special populations like children, infants, pregnant women or elderly, where the administering of higher amounts of radioactivity is prohibited [9]. Also, the technology could be applied to study the ADME fate of entities with a very long half-life, like for example biologics [38] or modified biologics like antibody-drug conjugates.…”

Section: Future Perspectivementioning

confidence: 99%

Evaluation of cAMS for ¹⁴ C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

Lozac'h

Fahrni²,

Maria

et al. 2018

Bioanalysis

View full text Add to dashboard Cite

Aim:Although regulatory guidances require human metabolism information of drug candidates early in the development process, the human mass balance study (or hADME study), is performed relatively late. hADME studies typically involve the administration of a 14 C-radiolabelled drug where biological samples are measured by conventional scintillation counting analysis. Another approach is the administration of therapeutic doses containing a 14 C-microtracer followed by accelerator mass spectrometry (AMS) analysis, enabling hADME studies completion much earlier. Consequently, there is an opportunity to change the current drug development paradigm. Materials & methods: To evaluate the applicability of the MICADAScAMS method, we successfully performed: the validation of MICADAS-cAMS for radioactivity quantification in biomatrices and, a rat ADME study, where the conventional methodology was assessed against a microtracer MICADAS-cAMS approach. Results & discussion: Combustion AMS (cAMS) technology is applicable to microtracer studies. A favorable opinion from EMA to complete the hADME in a Phase I setting was received, opening the possibilities to change drug development. Keywords:In the scope of drug development, regulatory guidances encourage the early identification of relevant human metabolites [1][2][3]. A human ADME study that used radiolabeled drugs allows the identification of metabolites and the elucidation of key biotransformation pathways and clearance mechanisms in humans. However, due to the high study cost, the needs for a dosimetry assessment (which include a rat distribution investigation) and for a GMP manufacturing as well as the high attrition rates encountered in drug development, the conventional hADME is generally performed late in drug development (Phase II, see Supplementary Figure 1). The administered dose in a conventional hADME study can contain up to 3.7 mBq of radioactivity which is analysed by scintillation counting. To address the regulatory demands earlier, a first investigation of pharmacokinetics (PK) and excretion routes is typically performed with a radiolabeled drug in rodents. Subsequently, exploratory analysis of potentially relevant metabolites is investigated in early clinical samples (Phase I) without the use of radiolabel [4,5] (Supplementary Figure 1). However, the applied LC-MS methods can fail to identify unknown metabolites. If human-specific metabolites are generated in early clinical samples, these metabolites will not be detected in preclinical species using radiolabeled drug, and will not be discovered in humans until the radiolabeled human mass balance ADME study is completed. To address this gap, we propose to dose a normal, therapeutically relevant dose spiked with very low amounts of a radiotracer to healthy volunteers or patients in a Phase I setting. Thereafter, the mass balance, the excretion routes and levels of circulating metabolites in humans are determined by accelerator mass spectrometry (AMS) as suggested by Lappin and Garner [6,7].AMS is a highly sensit...

show abstract

“…The study was able to demonstrate tumor targeting, near optimal bioavailability, and low interindividual variability in PK in the four patients studied, thereby supporting further development. In 2015, the first 14 C‐labelled recombinant human protein (human recombinant placental alkaline phosphatase [hRESCAP], an endogenous anti‐inflammatory protein) was studied in a phase 0/phase I adaptive design study . Results demonstrated linear PK from microdose (53 μg) to therapeutic dose (5.3 mg).…”

Section: Emerging Applications Of Phase 0/microdosing Studiesmentioning

confidence: 99%

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

Burt¹,

Yoshida

Lappin

et al. 2016

Clinical Translational Sci

View full text Add to dashboard Cite

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Cited by 22 publications

References 23 publications

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

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

Evaluation of cAMS for ¹⁴ C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

Contact Info

Product

Resources

About

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Cited by 22 publications

References 23 publications

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

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

Evaluation of cAMS for 14 C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

Contact Info

Product

Resources

About

Evaluation of cAMS for ¹⁴ C Microtracer ADME Studies: Opportunities to Change the Current Drug Development Paradigm