To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure

Bridges, Arlene S.

Dees, E. Claire

Herendeen, Jill

Hertz, Daniel L.

Hull, J. Heyward

Rollins, Kristan

Walko, Christine M.

Watkins, Paul B.

Carolina Digital Repository

Pilot study of rosiglitazone asan in vivo probe of paclitaxelexposureDaniel L. Hertz,1 Christine M. Walko,1,2 Arlene S. Bridges,3J. Heyward Hull,1 Jill Herendeen,1,† Kristan Rollins,1,‡ Paul B. Watkins1& E. Claire Dees2,41UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics,University of North Carolina at Chapel Hill, Chapel Hill, NC, 2UNC Lineberger Comprehensive CancerCenter, Chapel Hill, NC, 3ADME Mass Spectrometry Center, Department of Pathology and LaboratoryMedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC and 4Department of Medicine,Division of Hematology-Oncology, School of Medicine, University of North Carolina at Chapel Hill,Chapel Hill, NC, USACorrespondenceDr E. Claire Dees MD, MSc, UNC CB7305,170 Manning Drive, 3rdFloor, Chapel Hill,NC 27599, USA.Tel.: (919) 843 7714Fax: (919) 966 9735E-mail: claire_dees@med.unc.edu----------------------------------------------------------------------†Current Address: Amgen, Thousand Oaks,CA, USA.‡United Therapeutics, Research TrianglePark, NC, USA.----------------------------------------------------------------------Keywordserythromycin breath test, in vivo probe,paclitaxel, rosiglitazone----------------------------------------------------------------------Received8 August 2011Accepted15 December 2011Accepted ArticlePublished Online22 December 2011WHAT IS ALREADY KNOWN ABOUTTHIS SUBJECT• Paclitaxel and rosiglitazone are primarilymetabolized by CYP2C8 and their in vitrometabolism by human liver microsomes iscorrelated. Probe assays that quantify thein vivo activity of CYP enzymes which areimportant in drug metabolism have beendeveloped for use in clinical pharmacologyresearch. A probe of CYP2C8 that is easy toadminister and interpret may be valuablefor individualized dosing of paclitaxel.WHAT THIS STUDY ADDS• This pilot study demonstrates for the firsttime that there is an in vivo correlationbetween paclitaxel and rosiglitazoneexposure. The finding, that a singlerosiglitazone plasma concentration afteroral dosing may explain significant variancein paclitaxel exposure, suggests thatrosiglitazone may satisfy the requirementsof a clinically useful in vivo probe. However,it is acknowledged that there is a need forfurther studies evaluating the use ofrosiglitazone as a CYP2C8 probe andquantifying the relationship, in order toguide dosing of narrow therapeutic indexdrugs metabolized primarily by CYP2C8,such as paclitaxel.AIMSTo evaluate the use of rosiglitazone and the erythromycin breath test(ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explaininter-individual variability in paclitaxel exposure.METHODSThe concentration of rosiglitazone at 3 h and ERMBT results wereincluded in a regression model to explain the variability in paclitaxelexposure in 14 subjects.RESULTSRosiglitazone concentration was significantly correlated with paclitaxelexposure (P = 0.018) while ERMBT had no predictive value (P = 0.47).CONCLUSIONSThe correlation between the exposure of rosiglitazone and paclitaxellikely reflects mutual dependence on the activity of CYP2C8.Rosiglitazone or similar agents may have value as in vivo probes ofCYP2C8 activity.British Journal of ClinicalPharmacologyDOI:10.1111/j.1365-2125.2012.04165.xBr J Clin Pharmacol / 74:1 / 197–200 / 197© 2011 The AuthorsBritish Journal of Clinical Pharmacology © 2011 The British Pharmacological SocietyIntroductionInterpatient variability in toxic and therapeutic response tochemotherapy, partially caused by differences in the activ-ity of the CYP450 enzyme system, is a substantial problemin cancer treatment. One emerging approach to character-ize a drug’s metabolism is through the use of a probe, amarker agent that shares the drug’s metabolic pathway.Probe-based tests to measure CYP450 phenotype thatare safe, easy to administer and quickly interpretablehave been developed for some enzymes [1] relevant toanti-cancer therapy but not all.Paclitaxel is one of the most effective chemotherapeu-tic agents used in the treatment of solid tumour malignan-cies. It is metabolized to inactive metabolites primarily byCYP2C8 with a contribution from CYP3A4 [2]. A probeassay that could explain the significant interpatient vari-ability in paclitaxel exposure might help clinicians selectmore appropriate doses for an individual patient to opti-mize efficacy and limit toxicity.The erythromycin breath test (ERMBT) has been widelyimplemented to measure hepatic CYP3A4 activity [3].However, there is no such probe for CYP2C8. Interestingly,the rates of rosiglitazone metabolism and paclitaxelhydroxylation have been shown to correlate in human livermicrosomes expressing CYP2C8 [4]. In healthy subjects, a2 mg oral dose of rosiglitazone is safe, >99% bioavailableand the plasma concentration at 3 h is highly predictive ofAUC(0,•) (r2 = 0.98) (Clarke, S, GlaxoSmithKline, personalcommunication), making rosiglitazone an attractive probecandidate.Despite the known in vitro correlation, rosiglitazonehas not been previously used as a probe for CYP2C8 topredict paclitaxel exposure in patients. In this study weused rosiglitazone and ERMBT as surrogates of CYP2C8and CYP3A4 activity, respectively, and hypothesizedthat the combination of these probes would partiallyexplain the variability in paclitaxel exposure in cancerpatients.MethodsThis study was conducted at the General Clinical ResearchCenter (GCRC) and approved by the Institutional ReviewBoard at UNC Chapel Hill. Eligible patients were >18 yearsold with solid tumour malignancies, were scheduled toreceive weekly paclitaxel and provided written informedconsent.On study day 1, the erythromycin breath test (ERMBT)was carried out as previously described [5].The percentageof the dose exhaled as 14C over 1 h (AUC(0,1 h)) was logetransformed and used as a measure of CYP3A4 activity.Next, each subject (all of whom fasted for >6 h) was admin-istered a 2 mg oral dose of rosiglitazone. A blood samplewas collected 3 h after dosing and plasma concentrationanalysis was performed as previously described [6] withan assay lower limit of quantification of 3 ng ml-1 and acoefficient of variation <15%.Approximately 6 h after the rosiglitazone dose, eachsubject was administered a 1 h infusion of paclitaxel(75 mg m-2 to 90 mg m-2) as per their standard treatment.Blood samples (7 ml) were collected prior to infusion and0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 18–24 h after the start ofinfusion. Limited sampling, shown to reasonably estimatepaclitaxel exposure [7], was employed for patient conve-nience.The 18–24 h sample was intended for estimation ofAUC(0,•), which was subsequently deemed unreliable dueto inadequate estimation of the terminal phase elimina-tion rates. Plasma was separated and stored at -80°Cbefore undergoing analysis via LC/MS/MS as previouslydescribed with an assay lower limit of quantification of10 nM and a coefficient of variation < 15%, to measure totalpaclitaxel concentration [8].Paclitaxel pharmacokinetic analysis was performed inWinNonlin Pro Version 5.2.1 (Pharsight Corp., MountainView, CA) using non-compartmental methods. AUC(0,6 h)was calculated using the linear trapezoidal method andloge transformed for use in the primary analysis. Prior tostatistical analysis, paclitaxel and rosiglitazone concentra-tion values were adjusted to correspond to standardizeddoses (81.4 and 1.11 mg, respectively) based on the studymean patient BSA (1.81 m2), to minimize variability due todifferences in doses received and patient size, and wereloge transformed. BSA was selected as the metric for bodycomposition based on the practice of dosing paclitaxel byBSA. All later discussion refers to dose-adjusted and loge-transformed values, except where indicated.Statistical analysis was conducted in SAS 9.2 (SAS Insti-tute Inc, Cary, NC) using a multiple linear regression modelwith rosiglitazone and ERMBT AUC(0,1 h) the independentvariables and paclitaxel AUC(0,6 h) the dependent vari-able. Descriptive statistics are reported as mean (SD ormin, max), as appropriate.ResultsTwenty patients with planned or ongoing weekly pacli-taxel treatment were enrolled. Demographic data for the14 subjects who had evaluable samples for paclitaxel phar-macokinetic analysis are displayed in Table 1. The dose-adjusted mean paclitaxel AUC(0,6 h) was 6787 (2506)ng ml-1 h, rosiglitazone concentration was 82.3 (26.0)ng ml-1 and ERMBT AUC(0,1 h) was 2.76% h-1 (1.17). Inthe two-variable regression model rosiglitazone was a sta-tistically significant predictor of paclitaxel AUC(0,6 h)(P = 0.019). However, ERMBT was not (P = 0.47). After exclu-sion of ERMBT, rosiglitazone alone explained about 38% ofthe variability in paclitaxel AUC(0,6 h) (r2 = 0.38, P = 0.018,Figure 1). In follow-up exploratory analyses no otherrelevant covariates (e.g., age, albumin, cancer type andShort report198 / 74:1 / Br J Clin Pharmacolsmoking status) significantly contributed to the model(data not shown).DiscussionIn this pilot study, a 3 h rosiglitazone plasma concentrationafter a 2 mg oral dose explained 38% of the variabilityin paclitaxel exposure. As expected, higher rosiglitazoneconcentrations were associated with increased paclitaxelexposure. For a variety of reasons, including drug trans-porters, absorption and compensatory metabolic path-ways, rosiglitazone may not be the optimal CYP2C8 probe.Other potential probes, such as pioglitazone which may bemore sensitive to changes in CYP2C8 activity, should alsobe considered for further clinical CYP2C8 probe research[9].Because this was a small pilot study, supportive analy-ses of the data were conducted to investigate the robust-ness of our findings; with results consistent with theprimary analysis. The correlation between paclitaxelAUC(0,6 h) and rosiglitazone without dose adjustment wasstatistically significant (r2 = 0.33, P = 0.029) while adjustingfor mean weight in kg instead of BSA strengthened thefindings modestly (r2 = 0.50, P = 0.004). The correlationbetween paclitaxel AUC(0,•) and AUC(0,6 h) was strong (r2= 0.92) and use of AUC(0,•) instead of AUC(0,6 h) did notmeaningfully change the results (r2 = 0.32, P = 0.034).Finally, an even better relationship was found (r2 = 0.51,P = 0.004) when paclitaxel AUC(0,6 h) and rosiglitazonewere rank transformed prior to analysis, suggesting thatthe findings did not result from the impact of a particularlyinfluential value.The highest rosiglitazone concentration seen was120 ng ml-1 while the reported Ki of rosiglitazone is1998 ng ml-1 [10]. Thus, same day administration of rosigli-tazone and paclitaxel is unlikely to have resulted in com-petitive enzyme inhibition. In a similar study ERMBTexplained 67% of the variability in clearance of docetaxel[3], which is metabolized exclusively by CYP3A4. Ourfinding that ERMBT was not predictive of paclitaxel clear-ance was disappointing, but consistent with other evi-dence that CYP2C8 is the primary enzyme responsible forpaclitaxel metabolism. It is also likely that a portion of ourunexplained variability can be attributed to the role ofdrug transporters in the pharmacokinetics of ERMBT andpaclitaxel [11]. It should also be noted that both rosiglita-zone and paclitaxel are substrates for P-glycoprotein[12, 13] and this may contribute to the correlation weobserved.In conclusion, this report supports further study ofrosiglitazone or similar agents as in vivo probes ofCYP2C8 activity in humans. This is the first report of an invivo association between rosiglitazone and paclitaxelexposure and supports the hypothesis that rosiglitazonemay be a reasonable probe for in vivo exposure toCYP2C8 substrates.Competing InterestsUNC has received research funding for various clinical trialsfrom GlaxoSmithKline and Bristol-Myers Squibb, themakers of rosiglitazone and paclitaxel.We would like to thank Steve Clarke of GlaxoSmithKlinefor his advice and help with the rosiglitazone assay. DLH,Table 1Subject demographic and clinical characteristicsStudy population (n = 14)GenderFemale 11 (79%)Male 3 (21%)EthnicityCaucasian 12 (86%)African American 1 (7%)Other 1 (7%)Age (years): Mean (min, max) 45.7 (25, 64)BSA: Mean (min, max) 1.81 m2 (1.51, 2.33)Cancer typeBreast 4 (29%)Lung 6 (43%)Melanoma 2 (14%)Ovarian 1 (7%)Other 1 (7%)Paclitaxel dose: Mean (min, max) 81.37 mg m-2 (75, 90)Concomitant chemotherapy*Herceptin 4 (29%)Carboplatin 6 (43%)None 4 (29%)*Neither agent is known to modulate CYP2C8 or CYP3A4 activity.9.49.29.08.88.68.48.28.03.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8r2 = 0.38, P = 0.018BSA-normalized LN Rosiglitazone Concentration at 3 Hours (ng/mL)Dose/BSA-normalized LN Paclitaxel  AUC(0,6) (h*ng/ml)Figure 1Relationship between loge rosiglitazone 3 h concentration (x-axis) andloge paclitaxel AUC(0,6 h) (y-axis) (n = 14). Concentrations of both drugswere adjusted to a standard (mean) dose per BSAShort reportBr J Clin Pharmacol / 74:1 / 199PharmD, is an American Foundation for PharmaceuticalEducation Pre-Doctoral Fellow in Clinical PharmaceuticalScience. This study was funded in part by UNC (LCCC Clinical/Translational Research Award), National Institutes of Health(K23RR16536)(ECD), and by General Clinical Research CentersProgram of Division of Research Resources, National Insti-tutes of Health (RR00046).REFERENCES1 Frye RF. Probing the world of cytochrome P450 enzymes.Mol Interv 2004; 4: 157–62.2 Sparreboom A, Huizing MT, Boesen JJB, Nooijen WJ,Beijnen JH, Tellingen OV. Isolation, purification, andbiological activity of mono- and dihydroxylated paclitaxelmetabolites from human feces. Cancer ChemotherPharmacol 1995; 36: 299–304.3 Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R,Baker LH. The effect of an individual’s cytochrome CYP3A4activity on docetaxel clearance. 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Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure: Short report

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Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure: Short report

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