Tutorial: Statistical analysis and reporting of clinical pharmacokinetic studies

Dunvald, Ann-Cathrine Dalgård; Iversen, Ditte B.; Svendsen, Andreas Ludvig Ohm; Agergaard, Katrine; Kuhlmann, Ida Berglund; Mortensen, Christina; Andersen, Nanna Elman; Järvinen, Erkka; Stage, Tore Bjerregaard

doi:10.1111/cts.13305

Cited by 11 publications

(11 citation statements)

References 13 publications

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“…Sample size was calculated with the aim to detect a difference of ≥ 30% of midazolam AUC with a power of 80%, a 2‐sided significance level of 5%, and expected a dropout rate of 20%. We conducted statistical and pharmacokinetic analysis, as previously described 19 . Briefly, demographic data, such as age and body mass index, are presented as medians with interquartile ranges (IQRs; 25th–75th percentiles) and ranges.…”

Section: Methodsmentioning

confidence: 99%

Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

Iversen,

Dunvald,

Jespersen

et al. 2023

Clin Pharma and Therapeutics

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Flucloxacillin is a widely used antibiotic. It is an agonist to the nuclear receptor PXR that regulates the expression of cytochrome P450 (CYP) enzymes. Treatment with flucloxacillin reduces warfarin efficacy and plasma concentrations of tacrolimus, voriconazole, and repaglinide. We conducted a translational study to investigate if flucloxacillin induces CYP enzymes. We also investigated if flucloxacillin induces its own metabolism as an autoinducer. We performed a randomized, unblinded, two‐period, cross‐over, clinical pharmacokinetic cocktail study. Twelve healthy adults completed the study. They ingested 1 g flucloxacillin 3 times daily for 31 days, and we assessed the full pharmacokinetics of the Basel cocktail drugs on days 0, 10, and 28, and plasma concentrations of flucloxacillin on days 0, 9, and 27. The 3D spheroid of primary human hepatocytes (PHHs) were exposed to flucloxacillin (concentration range: 0.15–250 μM) for 96 hours. Induction of mRNA expression, protein abundance, and enzyme activity of CYP enzymes were assessed. Flucloxacillin treatment reduced the metabolic ratio of midazolam (CYP3A4), (geometric mean ratio (GMR) 10 days (95% confidence interval (CI)): 0.75 (0.64–0.89)) and (GMR 28 days (95% CI): 0.72 (0.62–0.85)). Plasma concentrations of flucloxacillin did not change during 27 days of treatment. Flucloxacillin caused concentration‐dependent induction of CYP3A4 and CYP2B6 (mRNA, protein, and activity), CYP2C9 (mRNA and protein), CYP2C19 (mRNA and activity), and CYP2D6 (activity) in 3D spheroid PHH. In conclusion, flucloxacillin is a weak inducer of CYP3A4, which may lead to clinically relevant drug–drug interactions for some narrow therapeutic range drugs that are substrates of CYP3A4.

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Section: Methodsmentioning

confidence: 99%

Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

Iversen,

Dunvald,

Jespersen

et al. 2023

Clin Pharma and Therapeutics

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“…Recruitment was delayed due to the COVID-19 pandemic, and the trial prematurely ended on May 5 th , 2022, following the completion of trial subject number ten, thus fulfilling the predefined sample. Statistical and pharmacokinetic analyses were conducted as previously described (24). In brief, demographic data and pharmacokinetic parameters are shown as medians with interquartile ranges (IQR; 25 th -75 th percentiles) or geometric mean ratios (GMR) with 95% confidence intervals.…”

Section: Methodsmentioning

confidence: 99%

“…The formation clearances (CL f ) were estimated as [amount of metabolite in urine 0-6h ] over [AUC of substate 0-6h ], and renal clearances (CL R ) were calculated as [amount of substrate in urine 0-6h ] over [AUC of substate 0-6h ]. AUC was determined for glucose, insulin, and C-peptide using the same methods as the pharmacokinetic parameters (24).…”

Section: Methodsmentioning

confidence: 99%

“…AUC was determined for glucose, insulin, and C-peptide using the same methods as the pharmacokinetic parameters (24).…”

Section: Statistics and Pharmacokinetic Analysesmentioning

confidence: 99%

“…and renal clearances (CL R ) were calculated as [amount of substrate in urine 0-6h ] over [AUC of substate 0-6h ]. AUC was determined for glucose, insulin, and C-peptide using the same methods as the pharmacokinetic parameters (24).…”

Section: Statistics and Pharmacokinetic Analysesmentioning

confidence: 99%

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Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin – but not through altered drug metabolism in patients with type 2 diabetes

Dunvald

Nielsen

Olsen

et al. 2022

Preprint

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Aims Drug metabolism might be altered in patients with type 2 diabetes, and we have previously shown that initiation of glucose-lowering drugs might reduce the efficacy of warfarin. We aimed to evaluate the impact of initiation of glucose-lowering drugs on warfarin efficacy and drug metabolism using a translational approach. Methods First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Individuals initiating a glucose-lowering drug during warfarin treatment were identified and warfarin efficacy (International Normalized Ratio (INR)) was compared before and after initiation of glucose-lowering drugs, overall and stratified by response (change in HbA1c). Second, we conducted a clinical pharmacokinetic trial comprising individuals with treatment-naive type 2 diabetes. In a self-controlled design, patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and at follow-up after three and 12 weeks of treatment. Drug metabolism, glycemic control, and inflammation were assessed on each visit. Results: In the Danish and Scottish cohorts, initiating glucose-lowering drugs reduced warfarin efficacy (n=982 and n=44, respectively). INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference -0.26; 95% CI -0.35;-0.17) and from 2.33 to 2.13 in the Scottish cohort (-0.21; 95% CI -0.52;0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment (HbA1c reduction > 10 mmol/mol) with mean differences of -0.44 (95% CI -0.71;-0.18) and -0.40 (95% CI -1.06;0.26) in Denmark and Scotland, respectively. In the clinical pharmacokinetic trial (n=10), initiating metformin did not affect drug metabolism after three and 12 weeks of metformin treatment (geometric mean ratio of CYP3A4 metabolic ratio: 1.12 (95% CI: 0.95;1.32) and 1.16 (95% CI: 0.93;1.44), respectively). Glycemic control improved during treatment, while inflammation remained low and unchanged during treatment. Conclusion Initiation of glucose-lowering drugs among chronic warfarin users is associated with a reduction in INR, particularly among individuals with a large decrease in HbA1c. However, this effect seems unrelated to CYP enzyme activity and warfarin drug metabolism. Registry number ClinicalTrials.gov identifier NCT04504045.

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Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy

Dunvald,

Søltoft,

Sheetal

et al. 2023

Eur J Clin Pharmacol

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Background Inflammation suppresses cytochrome P450 (CYP) enzyme activity, and single-dose interleukin 6 receptor antagonists (anti-IL-6R) reverse this effect. Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis. Methods In a clinical pharmacokinetic trial, the Basel cocktail was administered before and after 3 and 12 weeks of anti-IL-6R therapy to assess CYP enzyme activity (registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021). In a retrospective study, the 4β-hydroxycholesterol/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy. The control group was patients initiating a tumor necrosis factor alfa (TNF-α) inhibitor. Results In the clinical pharmacokinetic trial (n = 3), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and Cmax indicate a weak impact on CYP3A4 activity after 3 weeks of anti-IL-6R therapy compared to baseline (AUC geometric mean ratio (GMR): 0.80, 95% CI: 0.64–0.99 and Cmax GMR: 0.58, 95% CI: 0.37–0.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72–1.46 and Cmax GMR 1.03, 95% CI 0.72–1.47). No effect on the 4β-hydroxycholesterol/cholesterol ratio was observed in the retrospective study. Conclusion Based on sparse data from three patients, continuous anti-IL-6R therapy seems to cause an acute but transient increase in CYP3A4 activity in rheumatoid arthritis patients, which may be due to a normalization of the inflammation-suppressed CYP activity. Further studies are warranted to understand the mechanism behind this putative transient effect. Trial registration Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.

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Tutorial: Statistical analysis and reporting of clinical pharmacokinetic studies

Cited by 11 publications

References 13 publications

Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin – but not through altered drug metabolism in patients with type 2 diabetes

Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy

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