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Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1’-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2–3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28–30 h followed by a steep drop to almost baseline within 1–2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, −70.6%, and −61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected. Clinical Trial Registration The trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14).

Purpose To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine. Methods An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction). To prevent degradation of the uncoated omeprazole microdose, sodium bicarbonate buffer was administered. The pharmacokinetics of omeprazole and its 5-hydroxy-metabolite were assessed as well as the pharmacokinetics of midazolam and yohimbine to estimate CYP3A4 and CYP2D6 activity. Results Calculated pharmacokinetic parameters after administration of 100 µg and 20 mg omeprazole in healthy subjects suggest dose proportionality. Omeprazole clearance was significantly decreased by fluconazole from 388 [95% CI: 266–565] to 47.2 [42.8–52.0] mL/min after 20 mg omeprazole and even further after 100 µg omeprazole (29.4 [24.5–35.1] mL/min). Rifampicin increased CYP2C19-mediated omeprazole metabolism. The omeprazole hydroxylation index was significantly related to omeprazole clearance for both doses. Both fluconazole and rifampicin altered CYP3A4 activity whereas no change of CYP2D6 activity was observed at all. Conclusions Microdosed oral omeprazole is suitable to determine CYP2C19 activity, also during enzyme inhibition and induction. However, the administration of sodium bicarbonate buffer also had a small influence on all victim drugs used. Trial registration EudraCT: 2017–004270-34.

Purpose We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. Methods In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography–tandem mass spectrometry methods. Results Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37–1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26–1.51), edoxaban to 2.03 (1.84–2.24), and rivaroxaban to 1.44 (1.27–1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). Conclusion Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. Trial Registration EudraCT Number: 2018-002490-22

Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to

Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied.This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine.New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Preemptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.

Purpose The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF. Methods Midazolam doses of 0.03 and 3 mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2 min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers. Results The relative bioavailability of ODF-IS 0.03 mg was 102% (90% confidence interval: 89.4–116) compared to oral solution and for 3 mg 101% (86.8–116). Cmax of ODF-IS 0.03 mg was 95.5% (83.2–110) compared to oral solution and 94.3% (78.2–114) after 3 mg. Absolute bioavailability of ODF-IS 0.03 mg was 24.9% (21.2–29.2) and for 3 mg 28.1% (23.4–33.8) (oral solution: 0.03 mg: 24.4% (22.0–27.1); 3 mg: 28.0% (25.0–31.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03 mg: 61.4%; 3 mg: 44.1%; both p Conclusion This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC0–∞ in both doses was bioequivalent to the administration of an oral solution. However, Cmax of the therapeutic dose of ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability. (Trial Registration EudraCT: 2020–003984-24, August 10, 2020).

The small-molecule drug voriconazole (VRC) shows a complex and not yet fully understood metabolism. Consequently, its in vivo pharmacokinetics are challenging to predict, leading to therapy failures or adverse events. Thus, a quantitative in vitro characterization of the metabolism and inhibition properties of VRC for human CYP enzymes was aimed for. The Michaelis–Menten kinetics of voriconazole N-oxide (NO) formation, the major circulating metabolite, by CYP2C19, CYP2C9 and CYP3A4, was determined in incubations of human recombinant CYP enzymes and liver and intestine microsomes. The contribution of the individual enzymes to NO formation was 63.1% CYP2C19, 13.4% CYP2C9 and 29.5% CYP3A4 as determined by specific CYP inhibition in microsomes and intersystem extrapolation factors. The type of inhibition and inhibitory potential of VRC, NO and hydroxyvoriconazole (OH–VRC), emerging to be formed independently of CYP enzymes, were evaluated by their effects on CYP marker reactions. Time-independent inhibition by VRC, NO and OH–VRC was observed on all three enzymes with NO being the weakest and VRC and OH–VRC being comparably strong inhibitors of CYP2C9 and CYP3A4. CYP2C19 was significantly inhibited by VRC only. Overall, the quantitative in vitro evaluations of the metabolism contributed to the elucidation of the pharmacokinetics of VRC and provided a basis for physiologically-based pharmacokinetic modeling and thus VRC treatment optimization.

BACKGROUND: Five-day oral therapies against early COVID-19 infection have recently been conditionally approved in Europe. In the drug combination nirmatrelvir + ritonavir (nirmatrelvir/r), the active agent, nirmatrelvir, is made bioavailable in clinically adequate amounts by the additional administration of a potent inhibitor of its first-pass metabolism by way of cytochrome P450 [CYP] 3A in the gut and liver. In view of the central role of CYP3A in the clearance of many different kinds of drugs, and the fact that many patients with COVID-19 are taking multiple drugs to treat other conditions, it is important to assess the potential for drug interactions when nirmatrelvir/r is given, and to minimize the risks associated with such interactions. METHODS: We defined the interaction profile of ritonavir on the basis of information derived from two databases (Medline, GoogleScholar), three standard electronic texts on drug interactions, and manufacturer-supplied drug information. We compiled a list of drugs and their potentially relevant interactions, developed a risk min - imization algorithm, and applied it to the substances in question. We also compiled a list of commonly prescribed drugs for which there is no risk of interaction with nirmatrelvir/r. RESULTS: Out of 190 drugs and drug combinations, 57 do not need any special measures when given in combination with brief, low-dose ritonavir treatment, while 15 require dose modification or a therapeutic alternative, 8 can be temporarily discontinued, 9 contraindicate ritonavir use, and 102 should preferably be combined with a different treatment. CONCLUSION: We have proposed measures that are simple to carry out for the main types of drug that can interact with ritonavir. These measures can be implemented under quarantine conditions before starting a 5-day treatment with nirmatrelvir/r.

Purpose Voriconazole is a therapeutically challenging antifungal drug associated with high interindividual pharmacokinetic variability. As a prerequisite to performing clinical trials using the minimally-invasive sampling technique microdialysis, a comprehensive in vitro microdialysis characterization of voriconazole (VRC) and its potentially toxic N-oxide metabolite (NO) was performed. Methods The feasibility of simultaneous microdialysis of VRC and NO was explored in vitro by investigating the relative recovery (RR) of both compounds in the absence and presence of the other. The dependency of RR on compound combination, concentration, microdialysis catheter and study day was evaluated and quantified by linear mixed-effects modeling. Results Median RR of VRC and NO during individual microdialysis were high (87.6% and 91.1%). During simultaneous microdialysis of VRC and NO, median RR did not change (87.9% and 91.1%). The linear mixed-effects model confirmed the absence of significant differences between RR of VRC and NO during individual and simultaneous microdialysis as well as between the two compounds (p > 0.05). No concentration dependency of RR was found (p = 0.284). The study day was the main source of variability (46.3%) while the microdialysis catheter only had a minor effect (4.33%). VRC retrodialysis proved feasible as catheter calibration for both compounds. Conclusion These in vitro microdialysis results encourage the application of microdialysis in clinical trials to assess target-site concentrations of VRC and NO. This can support the generation of a coherent understanding of VRC pharmacokinetics and its sources of variability. Ultimately, a better understanding of human VRC pharmacokinetics might contribute to the development of personalized dosing strategies.

IntroductionChildhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children Methods and analysisSystematic review methodology will be applied to identify, select and extract data from published plasma guided dosing studies conducted in a paediatric leukaemia cohort. Databases (eg, Ovid Embase, Ovid MEDLINE, Ovid Cochrane) and clinical trial registries (CENTRAL, ClinicalTrials.gov and ISRCTN) will be used to perform the systematic literature search (up until February 2021). Only full empirical studies will be included, with primary clinical outcomes (progression-free survival, toxicities, minimal residual disease status, complete cytogenetic response, partial cytogenetic response and major molecular response) being used to decide whether the study will be included. The quality of included studies will be undertaken, with a subgroup analysis where appropriate.Ethics and disseminationThis systematic review will not require ethics approval as there will not be collection of primary data. Findings of this review will be made available through publications in peer-reviewed journals and conference presentations. Gaps will be identified in current literature to inform future-related research.PROSPERO registration numberCRD42021225045.

IntroductionDirect oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein thrombosis or non-valvular atrial fibrillation. Paediatric patients might benefit as well from DOACs because the simplicity and convenience of their use is likely to decrease physical and psychological stress related to invasive procedures associated with phenprocoumon and heparin therapy. Thus, it is expected that the future use of DOACs will ultimately improve compliance and overall safety of anticoagulant therapies in paediatric populations. To assure safe and effective use the clinical pharmacology and pharmacokinetics (PK) of these drugs need to be evaluated in children.Methods and analysisThis study is a single-centre, open-label, clinical trial in a paediatric population with non-cyanotic congenital heart defects. After having obtained informed consent from the parents, each participant will receive a single oral administration of a drinkable solution of a microdose cocktail of three FXa inhibitors consisting of apixaban (12.5 µg), rivaroxaban (12.5 µg), edoxaban (50 µg), plus a microdose of the two probe drugs midazolam (10 µg) and yohimbine (25 µg). Serial blood samples (n=up to 20) will be collected at specified time points before and up to 25 hours after cocktail administration. The primary PK endpoint will be the area under the plasma concentration time curve of apixaban, rivaroxaban and edoxaban. Secondary PK outcomes will be Cmax, tmax, t1/2, Cl/F and Vss/F. Safety and tolerability of the microdose cocktail will be evaluated as well by a collection of adverse events.EthicsThis study has been approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University.DisseminationStudy results will be presented at international scientific meetings and published in peer-reviewed journals.Trial registration numberEudraCT 2019-001759-38 16, DRKS00021455.

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in adults with symptomatic chronic HF and ejection fraction less than 45%. Guidelines recommend short-acting nitrates, such as sublingual nitroglycerin, for the treatment of acute angina pectoris in patients with chronic coronary syndromes (CCSs), common comorbidities in HF. We evaluated safety, tolerability, and the pharmacodynamic interaction between vericiguat and nitroglycerin, coadministered in patients with CCSs. In this phase Ib, double-blind, randomized, multicenter study, 36 patients with CCSs received either vericiguat 2.5 mg (up-titrated every 2 weeks to 5 mg and 10 mg) or placebo. Patients also received nitroglycerin (0.4 mg sublingual). In total, 31 patients completed the study (vericiguat + nitroglycerin, n = 21; placebo + nitroglycerin, n = 10). There was no increase in treatment-emergent adverse events (TEAEs) with vericiguat + nitroglycerin vs. placebo + nitroglycerin; three patients discontinued due to TEAEs (vericiguat + nitroglycerin, n = 1; placebo + nitroglycerin, n = 2). Decreases in mean blood pressure (BP; 6-10 mmHg systolic BP (SBP); 4-6 mmHg diastolic BP (DBP)) were independent of vericiguat exposure and occurred to a similar extent at trough and peak concentrations with all vericiguat doses and placebo. Coadministration of vericiguat with nitroglycerin in patients with CCSs was well tolerated, and the combination is unlikely to cause significant adverse effects beyond those known for nitroglycerin.

Ketoconazole is a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and of P-glycoprotein (P-gp) and is often used as an index inhibitor especially for CYP3A4-mediated drug metabolism. A preliminary physiologically based pharmacokinetic (PBPK) model for drug-drug interactions indicated possible involvement of a metabolite to the perpetrator potential of ketoconazole. Still unknown for humans, in rodents, N-deacetyl ketoconazole (DAK) has been identified as the major ketoconazole metabolite. We therefore investigated in vitro, whether DAK also inhibits the human CYPs and drug transporters targeted by ketoconazole and quantified DAK in human plasma from healthy volunteers after receiving a single oral dose of 400 mg ketoconazole. Our data demonstrated that DAK also inhibits CYP3A4 (2.4-fold less potent than ketoconazole), CYP2D6 (13-fold more potent than ketoconazole), CYP2C19 (equally potent), P-gp (3.4-fold less potent than ketoconazole), breast cancer resistance protein (more potent than ketoconazole) and organic anion transporting polypeptide 1B1 and 1B3 (7.8-fold and 2.6-fold less potent than ketoconazole). After a single oral dose of 400 mg ketoconazole, maximum concentrations of DAK in human plasma were only 3.1 ‰ of the parent compound. However, assuming that DAK also highly accumulates in the human liver as demonstrated for rodents, inhibition of the proteins investigated could also be conceivable in vivo. In conclusion, DAK inhibits several CYPs and drug transporters, which might contribute to the perpetrator potential of ketoconazole.