Mass balance and metabolism of the antimalarial pyronaridine in healthy volunteers

Morris, Carrie A.; Dueker, Stephen R.; Lohstroh, Peter N.; Wang, Liquan; Fang, Xinping; Jung, Donald; López-Lázaro, Luis; Baker, Mark; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Pokorny, Rolf; Shin, Jangsik; Fleckenstein, Lawrence

doi:10.1007/s13318-014-0182-0

Cited by 18 publications

(22 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The question ‘Can the results from an AMS‐enabled absorption, metabolism and excretion (AME) study be submitted to regulators as definitive data?’ is often asked. The short answer is ‘Yes’, this has been done successfully for many compounds, including some examples where the data have also been published . In principal, it is possible to use data from a 14 C microtracer‐enhanced FIH in this way.…”

Section: Clinical Study Designmentioning

confidence: 99%

Adding value through accelerator mass spectrometry‐enabled first in human studies

Seymour

2016

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

Accelerator mass spectrometry (AMS) is an ultra-sensitive technique for the analysis of radiocarbon. It is applicable to bioanalysis of any C-labelled analyte and any sample type. The increasing body of data generated using LC+AMS indicates that the methodology is robust and reliable, and capable of meeting the same validation criteria as conventional bioanalytical techniques. Because it is a tracer technique, AMS is capable of discriminating between an administered radiolabelled dose and endogenous compound or non-radiolabelled compound administered separately. This paper discusses how it can be used to enhance the design of first in human (FIH) clinical studies and generate significant additional data, including: fundamental pharmacokinetics (CL and V), absolute bioavailability, mass balance, routes and rates of excretion, metabolic fate (including first-pass metabolism, identification of biliary metabolites and quantitative data to address metabolite safety testing issues), and tissue disposition of parent compound and metabolites. Because the C-labelled microtracer dose is administered at the same time as a pharmacologically relevant non-radiolabelled dose, there is no concern about dose-linearity. However the mass of the microtracer dose itself is negligible and therefore does not affect the outcome of the FIH study. The addition of microtracer doses to a FIH study typically requires little additional expense, apart from the AMS analytics, making the approach cost-effective. It can also save significant time, compared to conventional approaches, and, by providing reliable human in vivo data as early as possible, prevent unnecessary expenditure later in drug development.

show abstract

Section: Clinical Study Designmentioning

confidence: 99%

Adding value through accelerator mass spectrometry‐enabled first in human studies

Seymour

2016

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

show abstract

“…It was likely that the low mass balance recovery was either from lack of fecal sample homogeneity leading to lower recovery in feces or from some error in urine sample processing, which had shown some erroneous results for predose urine samples, casting doubts on the total urine radioactivity recovery. Reanalysis of 0-72/96 hours postdose urine samples, with high radioactivity, was conducted using LSC to avoid any potential contamination of the ion source, which provided a higher concentration of drug output in the urine than did the AMS sucrose dilution method 27,28 and largely explained the apparent low recovery of [ 14 C]-radioactivity within the urine voids.…”

Section: Radioactivity Determination In Whole Blood Plasma Urine Amentioning

confidence: 99%

Absorption, Distribution, and Excretion of the Investigational Agent Orteronel (TAK‐700) in Healthy Male Subjects: A Phase 1, Open‐Label, Single‐Dose Study

Suri

Pusalkar

et al. 2016

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

This study evaluated the absorption, distribution, and excretion of orteronel, an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. Six healthy male subjects received a single 400-mg dose of radiolabeled [(14) C]-orteronel (18.5 kBq). The pharmacokinetics of [(14) C]-radioactivity, orteronel, and the primary metabolite M-I were characterized by ultra-performance liquid chromatography-tandem mass spectrometry, and mass balance recovery of [(14) C]-radioactivity was determined by liquid scintillation counting and accelerator mass spectrometry. Median time to maximum observed concentration of [(14) C]-radioactivity was 2.5 hours (plasma/whole blood) and of orteronel was 1 hour (plasma). Mean terminal half-life for [(14) C]-radioactivity in plasma and whole blood was 9.46 and 7.39 hours, respectively. For [(14) C]-radioactivity, the geometric mean whole blood-to-plasma ratios for maximum observed plasma/whole-blood concentration, area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUC0-last ), and AUC0-inf (AUC from time 0 to infinity) were 1.04, 0.92, and 0.93, respectively. Dose recovery accounted for 95.9% of the administered orteronel dose; the majority of excretion occurred by 96 hours postdose. The principal excretion route was via urine (mean, 77.5%; including 49.7% unchanged drug and 16.3% M-I) compared with 18.4% via feces. Three mild adverse events were reported; none were considered serious or related to orteronel.

show abstract

“…In microdosing studies [phase 0 clinical trials, exploratory investigational new drug (IND) studies [, the labeled compound is administered solely at a dose \1 % of the expected pharmacologically active dose, with a maximum of 0.1 mg [5]. This allows investigation of clinical pharmacokinetics, including mass balance and metabolite profiling, earlier in development, before resources are spent on extensive preclinical drug metabolism and pharmacokinetics (DMPK) and toxicity testing [6][7][8][9]. Microdosing is also used in cases where pharmacokinetics cannot confidently be predicted from preclinical animal species, or to investigate or confirm metabolic routes in humans.…”

Section: Introductionmentioning

confidence: 99%

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

Mass balance and metabolism of the antimalarial pyronaridine in healthy volunteers

Cited by 18 publications

References 8 publications

Adding value through accelerator mass spectrometry‐enabled first in human studies

Adding value through accelerator mass spectrometry‐enabled first in human studies

Absorption, Distribution, and Excretion of the Investigational Agent Orteronel (TAK‐700) in Healthy Male Subjects: A Phase 1, Open‐Label, Single‐Dose Study

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

Contact Info

Product

Resources

About