Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Xu, Yang; Zhou, Yihong; Hayashi, Mike; Shou, Magang; Skiles, Gary L.

doi:10.1124/dmd.111.038067

Cited by 44 publications

(51 citation statements)

References 67 publications

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“…Fahmi et al (2012) also reported an overprediction for sulfinpyrazone using midazolam-RIS calibration curves in DPX2 cells. As midazolam exhibits a very high fraction of metabolized CYP3A (f m , CYP3A ), it is likely more susceptible to CYP3A4 induction than victim drugs (e.g., R-warfarin) cleared by additional pathways (Ripp et al, 2006;Xu et al, 2011). These findings underscore the use of midazolam as a preferential and sensitive clinical probe for DDI investigations.…”

Section: Tablementioning

confidence: 58%

Evaluation of Calibration Curve–Based Approaches to Predict Clinical Inducers and Noninducers of CYP3A4 with Plated Human Hepatocytes

Zhang

Callendrello

et al. 2014

Drug Metab Dispos

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Cytochrome P450 (P450) induction is often considered a liability in drug development. Using calibration curve-based approaches, we assessed the induction parameters R 3 (a term indicating the amount of P450 induction in the liver, expressed as a ratio between 0 and 1), relative induction score, C max /EC 50 , and area under the curve (AUC)/F 2 (the concentration causing 2-fold increase from baseline of the doseresponse curve), derived from concentration-response curves of CYP3A4 mRNA and enzyme activity data in vitro, as predictors of CYP3A4 induction potential in vivo. Plated cryopreserved human hepatocytes from three donors were treated with 20 test compounds, including several clinical inducers and noninducers of CYP3A4. After the 2-day treatment, CYP3A4 mRNA levels and testosterone 6b-hydroxylase activity were determined by real-time reverse transcription polymerase chain reaction and liquid chromatographytandem mass spectrometry analysis, respectively. Our results demonstrated a strong and predictive relationship between the extent of midazolam AUC change in humans and the various parameters calculated from both CYP3A4 mRNA and enzyme activity. The relationships exhibited with non-midazolam in vivo probes, in aggregate, were unsatisfactory. In general, the models yielded better fits when unbound rather than total plasma C max was used to calculate the induction parameters, as evidenced by higher R 2 and lower root mean square error (RMSE) and geometric mean fold error. With midazolam, the R 3 cut-off value of 0.9, as suggested by US Food and Drug Administration guidance, effectively categorized strong inducers but was less effective in classifying midrange or weak inducers. This study supports the use of calibration curves generated from in vitro mRNA induction response curves to predict CYP3A4 induction potential in human. With the caveat that most compounds evaluated here were not strong inhibitors of enzyme activity, testosterone 6b-hydroxylase activity was also demonstrated to be a strong predictor of CYP3A4 induction potential in this assay model.

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Section: Tablementioning

confidence: 58%

Evaluation of Calibration Curve–Based Approaches to Predict Clinical Inducers and Noninducers of CYP3A4 with Plated Human Hepatocytes

Zhang

Callendrello

et al. 2014

Drug Metab Dispos

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“…Subjects received daily dosing of rifampicin 600 mg for 8 days to maximize the induction effect on CYP3A4 [10]. Selumetinib 75 mg was administered in a fasted state; subjects were maintained in a fasted state overnight, for a minimum of 10 h until 4 h post-dose.…”

Section: Methodsmentioning

confidence: 99%

Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials

Dymond

Martín

et al. 2016

Eur J Clin Pharmacol

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PurposeTwo phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib.MethodsIn study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1–11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2–11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment. In study B (n = 22), subjects received a single dose of selumetinib 75 mg (day 1) then rifampicin 600 mg/day (days 4–14) plus a single dose of selumetinib 75 mg on day 12. Pharmacokinetic analysis and safety assessments were performed.ResultsSelumetinib co-administered with itraconazole, fluconazole (selumetinib staggered 4 h after itraconazole/fluconazole dose), or rifampicin was well tolerated. Selumetinib exposure was higher when co-administered with itraconazole or fluconazole (area under the plasma concentration-time curve (AUC) increased by 49 and 53%, respectively; maximum plasma concentration (C max) increased by 19 and 26%, respectively) but lower when co-dosed with rifampicin (AUC and C max decreased by 51 and 26%, respectively) versus selumetinib dosed alone. Co-administration with itraconazole or rifampicin decreased N-desmethyl selumetinib AUC(0–t) (11 and 55%, respectively), and C max (25 and 18%, respectively), with fluconazole, AUC(0–t) increased by 40%, but there was no effect on C max.ConclusionsCo-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP3A4 inducers will likely reduce its exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-016-2153-7) contains supplementary material, which is available to authorized users.

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“…Extrapolation of these short-term results to prolonged coadministration should be considered. On the basis of simulations of trial designs for CYP3A4 inducers (18,19), an assumed CYP3A4 turnover half-life of 36 h (20), the short half-life of prednisone, and the high prednisone dosage used in this study, there is no evidence to suggest that continued prednisone dosing beyond 10 days would have resulted in a significant increase in induction of metabolism that would cause a clinically significant decrease in DTG exposure.…”

Section: Discussionmentioning

confidence: 99%

Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

Song

Borland

Chen

et al. 2013

Antimicrob Agents Chemother

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Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.)T argeting HIV integration of viral DNA into the human genome has yielded a new class of antiretroviral agents, the HIV integrase inhibitors, which have been used successfully in combination with other antivirals to suppress HIV replication (1-3). Dolutegravir (DTG; ViiV Healthcare, Research Triangle Park, NC) is a once-daily HIV integrase inhibitor with effective antiviral activity and a favorable safety profile. Dolutegravir is metabolized primarily by UDP-glucuronosyltransferase (UGT), with CYP3A4 playing a minor role (4). Dolutegravir has a favorable drug interaction profile, with few dose adjustments required, although potent enzyme inducers can reduce DTG exposure (5).Prednisone is used to treat a number of AIDS-related illnesses, such as immune reconstitution inflammatory syndrome, Pneumocystis jirovecii pneumonia, AIDS-related lymphoma, and concomitant diseases such as asthma, chronic obstructive pulmonary disease, autoimmune/rheumatologic disease, inflammatory bowel disease, and cancers (6-10).Some corticosteroids have been shown to decrease the exposure of UGT and CYP3A4 substrates (11, 12), depending on the choice of steroids, dose, and duration. Daily prednisone treatment of 40 mg/m 2 for 28 days increased etoposide clearance by 62% compared with placebo (13). Six-day treatment with low-dose prednisone (10 mg twice daily) modestly decreased metronidazole exposure, by 31% (14). Treatment with another corticosteroid, dexamethasone, at 1.5 mg for 4 days reduced oral triazolam AUC by 19% (15), whereas 2-day dexamethasone treatment at 24 mg per day decre...

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Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Cited by 44 publications

References 67 publications

Evaluation of Calibration Curve–Based Approaches to Predict Clinical Inducers and Noninducers of CYP3A4 with Plated Human Hepatocytes

Evaluation of Calibration Curve–Based Approaches to Predict Clinical Inducers and Noninducers of CYP3A4 with Plated Human Hepatocytes

Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials

Effect of Prednisone on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir

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