A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions.

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug-drug interaction, hepatic dysfunction, population PK, exposure-response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations.

Efficacy and safety of vismodegib in advanced basal-cell carcinoma.

BACKGROUND: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS: In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS: Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

Daily dosing of vismodegib to steady state does not prolong the QTc interval in healthy volunteers.

INTRODUCTION: Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval. METHODS AND RESULTS: Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed. This dedicated QTc study was powered to exclude a 20-millisecond change from the baseline QTc interval. The subjects were administered daily oral 150 mg of vismodegib for 7 days, or a single dose of 400 mg of moxifloxacin, with corresponding matching placebos. The upper limits of the 90% confidence intervals for the difference in ΔQTcF between vismodegib and placebo at steady state were <20 milliseconds at all timepoints with a maximum of 10 milliseconds at 12 hours postdose. Exposure-response analysis yielded an estimated slope equal to 0.11 ms/µM, which was not statistically significant. After a single dose of moxifloxacin was administered, the lower limits of the 90% confidence interval of the difference in ΔQTcF between moxifloxacin and placebo were >5 milliseconds from 1-12 hours postdose, thereby establishing assay sensitivity. CONCLUSIONS: There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state.

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS: This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIM: Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. METHODS: Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. RESULTS: Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION: Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.

A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry.

Vismodegib (GDC-0449), a small-molecule Hedgehog pathway inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. The purpose of the study presented here was to determine routes of elimination and the extent of vismodegib metabolism, including assessment and identification of metabolites in plasma, urine, and feces. Six healthy female subjects of nonchildbearing potential were enrolled; each received a single 30-ml oral suspension containing 150 mg of vismodegib with 6.5 µg of [(14)C]vismodegib to yield a radioactivity dose of approximately 37 kBq (1000 nCi). Plasma, urine, and feces samples were collected over 56 days to permit sample collection for up to 5 elimination half-lives. Nonradioactive vismodegib was measured in plasma using liquid chromatographic-tandem mass spectrometry, and total radioactivity in plasma, urine, and feces was measured using accelerator mass spectrometry. Vismodegib was slowly eliminated by a combination of metabolism and excretion of parent drug, most of which was recovered in feces. The estimated excretion of the administered dose was 86.6% on average, with 82.2 and 4.43% recovered in feces and urine, respectively. Vismodegib was predominant in plasma, with concentrations representing >98% of the total circulating drug-related components. Metabolic pathways of vismodegib in humans included oxidation, glucuronidation, and uncommon pyridine ring cleavage. We conclude that vismodegib and any associated metabolic products are mainly eliminated through feces after oral administration in healthy volunteers.

Pharmacokinetics of Ampreloxetine, a Norepinephrine Reuptake Inhibitor, in Healthy Subjects and Adults with Attention-Deficit/Hyperactive Disorder or Fibromyalgia Pain.

BACKGROUND AND OBJECTIVE: Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development. METHODS: We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2-50 mg. RESULTS: Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30-40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects. CONCLUSIONS: The population pharmacokinetic model effectively described the plasma concentration-time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).

Leveraging innovative technology to generate drug response phenotypes for the advancement of biomarker-driven precision dosing.

Although traditional approaches to biomarker discovery have elucidated key molecular markers that have improved drug selection (precision medicine), the discovery of biomarkers that inform optimal dose selection (precision dosing) continues to be a challenge in many therapeutic areas. Larger and more diverse study populations are necessary to discover additional biomarkers that provide the resolution needed for a more tailored dose. To generate and accommodate large datasets of drug response phenotypes, time- and cost-efficient strategies are necessary. In particular, a multitude of technological advances that originated for purposes outside of biomedical research (electronic health records, direct-to-consumer genetic testing, social media, mobile devices, and machine learning) have made it easier to communicate, connect, and gather information from consumers. Although these technologies have been used with success in the health sciences for an array of purposes, these resources have not been fully capitalized on for precision dosing. This perspective will touch on how these innovations can be used as data sources, data collection tools, and data processing tools for drug-response phenotypes with a unique focus on advancing biomarker-driven precision dosing.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme.

BACKGROUND AND AIMS: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC. METHODS: TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. RESULTS: TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. CONCLUSION: Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686].

Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic impairment.

PURPOSE: Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study. METHODS: Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili) < upper limit of normal (ULN)], mild (ULN < bili ≤ 1.5 × ULN), moderate (1.5 × ULN < bili ≤ 3×ULN), and severe (3 × ULN < bili < 10 × ULN) dysfunction. Patients received oral vismodegib 150 mg daily. Plasma PK samples on days 1, 3, 5, and 8 were collected. Vismodegib therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent. RESULTS: Thirty-one patients were accrued: nine normal, eight mild, eight moderate, and six severe. Four patients experienced dose-limiting toxicity of hyperbilirubinemia on study: one in the moderate cohort and three in the severe cohort. Six patients died within 30 days after the last dose of vismodegib. All deaths were attributed to disease progression. Observed maximal and average steady-state concentrations and AUC of vismodegib at steady state (day 8) were similar across cohorts. Average AAG concentrations in patients with hepatic impairment were comparable to those of patients with normal hepatic function. CONCLUSIONS: Hepatic impairment does not appear to impact vismodegib PK, and therefore, dose adjustment is not necessary in this special population. The study was influenced by the high number of patients with hepatocellular carcinoma with advanced cirrhosis; rendering it difficult to draw any causal relationships between vismodegib exposure and the serious adverse events.

Cloning, tissue expression, and regulation of beagle dog CYP4A genes.

In addition to its function as a fatty acid hydroxylase, the peroxisome proliferator-activated receptor alpha (PPARalpha) target gene, CYP4A, has been shown to be important in the conversion of arachidonic acid to the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, suggesting a role for this enzyme in mediating vascular tone. In the present study, the cDNA sequence of beagle dog CYP4A37, CYP4A38, and CYP4A39 from the liver was determined. Open reading frame analysis predicted that CYP4A37, CYP4A38, and CYP4A39 each comprised 510 amino acids with approximately 90% sequence identity to one another, and approximately 71 and 78% sequence identity to rat CYP4A1 and human CYP4A11, respectively. PCR analysis revealed that the three dog CYP4A isoforms are expressed in kidney > liver >> lung >> intestine > skeletal muscle > heart. Treatment of primary dog hepatocytes with the PPARalpha agonists GW7647X and clofibric acid resulted in an increase in CYP4A37, CYP4A38, and CYP4A39 mRNA expression (up to fourfold), whereas HMG-CoA synthase mRNA expression was increased to a greater extent (up to 10-fold). These results suggest that dog CYP4A37, CYP4A38, and CYP4A39 are expressed in a tissue-dependent manner and that beagle dog CYP4A is not highly inducible by PPARalpha agonists, similar to the human CYP4A11 gene.

A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities.

The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure-response modeling methods.

A clinical drug-drug interaction study to evaluate the effect of a proton-pump inhibitor, a combined P-glycoprotein/cytochrome 450 enzyme (CYP)3A4 inhibitor, and a CYP2C9 inhibitor on the pharmacokinetics of vismodegib.

PURPOSE: The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics. METHODS: Cohorts included a control arm (n = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n = 24); itraconazole 200 mg (n = 22); or fluconazole 400 mg (n = 22). RESULTS: Area under the vismodegib concentration-time curve from zero to 24 h (AUC0-24h) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC0-24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib. CONCLUSION: The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug-drug interaction. CLINICALTRIALS. GOV IDENTIFIER: NCT01772290.

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug-drug interaction potential.

PURPOSE: Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). METHODS: This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 µg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8). RESULTS: The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 µM (range 7.93-62.4 µM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [≤8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (≤5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib. CONCLUSIONS: This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer.

PURPOSE: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC). EXPERIMENTAL DESIGN: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions. RESULTS: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab. CONCLUSIONS: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

Evaluation of food effect on pharmacokinetics of vismodegib in advanced solid tumor patients.

PURPOSE: Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). We conducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure. EXPERIMENTAL DESIGN: In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were C(max) and area under the curve (AUC(0-168)). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were C(max) and AUC(0-24). RESULTS: Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean C(max) and AUC(0-168) after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in C(max) or AUC(0-24) between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups. CONCLUSIONS: A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing.

Determination of unbound vismodegib (GDC-0449) concentration in human plasma using rapid equilibrium dialysis followed by solid phase extraction and high-performance liquid chromatography coupled to mass spectrometry.

A rapid equilibrium dialysis (RED) assay followed by a solid phase extraction (SPE) high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the quantitative determination of unbound vismodegib in human plasma was developed and validated. The equilibrium dialysis was carried out using 0.3 mL plasma samples in the single-use plate RED system at 37°C for 6h. The dialysis samples (0.1 mL) were extracted using a Strata-X-C 33u Polymeric Strong Cation SPE plate and the resulting extracts were analyzed using reverse-phase chromatography and positive electrospray ionization (ESI) mass spectrometry. The standard curve, which ranged from 0.100 to 100 ng/mL for vismodegib, was fitted to a 1/x(2) weighted linear regression model. The lower limit of quantitation (LLOQ, 0.100 ng/mL) was sufficient to quantify unbound concentrations of vismodegib after dialysis. The intra-assay precision of the LC-MS/MS assay, based on the four analytical QC levels (LLOQ, low, medium and high), was within 7.7% CV and inter-assay precision was within 5.5% CV. The assay accuracy, expressed as %Bias, was within ±4.0% of the nominal concentration values. Extraction recovery of vismodegib was between 77.9 and 84.0%. The assay provides a means for accurate assessment of unbound vismodegib plasma concentrations in clinical studies.

Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding.

PURPOSE: In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics. EXPERIMENTAL DESIGN: Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA. RESULTS: A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 µmol/L) and human serum albumin less strongly (K(D) = 120 µmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination. CONCLUSIONS: GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.

Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors.

PURPOSE: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. EXPERIMENTAL DESIGN: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. RESULTS: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. CONCLUSIONS: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.