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This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (CPK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles.PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL.ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.

This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.

PURPOSE The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.

Antibody-drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019. Despite their enormous promise, the therapeutic window for these ADCs remains relatively narrow, especially when compared with other oncology drugs, such as targeted therapies or checkpoint inhibitors. In this review, we provide a detailed overview of the five dosing regimen optimization strategies that have been leveraged to broaden the therapeutic window by mitigating the safety risks while maintaining efficacy. These include body weight cap dosing; treatment duration capping; dose schedule (e.g., dosing frequency and dose fractionation); response-guided dosing recommendations; and randomized dose-finding. We then discuss how the lessons learned from these studies can inform ADC development going forward. Informed application of these dosing strategies should allow researchers to maximize the safety and efficacy for next-generation ADCs.

Purpose The CD79b-targeted antibody–drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. Methods The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI‐142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. Results PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. Conclusion Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure–response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.

Introduction Outcomes remain poor in patients with diffuse large B cell lymphoma (DLBCL) who overexpress BCL-2 protein. We present population pharmacokinetics (PopPK) and exposure–response (ER) analyses for venetoclax (a selective BCL-2 inhibitor) administered with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed/refractory (R/R) and previously untreated (1L) non-Hodgkin lymphoma (NHL) from the phase 1b/2 CAVALLI study, to confirm dose selection for future studies. Methods Analyses included 216 patients with R/R or 1L NHL treated for eight 21-day cycles with 400–800 mg venetoclax (cycle 1: days 4–10; cycles 2–8: days 1–10) in combination with R for eight cycles and CHOP for 6–8 cycles. A legacy PopPK model for venetoclax was used to describe the observed data and provide post hoc PK parameters. Venetoclax steady-state exposure (AUCss) was used to predict clinical efficacy, safety, or tolerability. To isolate the effect of venetoclax, ER analyses referenced data from the R-CHOP arm of a historical control study, GOYA, in 1L DLBCL. Results There was no significant association between venetoclax AUCss and progression-free survival or complete response either for all-comers or the BCL-2-immunohistochemistry-positive subpopulation. No statistically significant trends were observed with venetoclax AUCss and the key grade ≥ 3 adverse events and serious adverse events. Similar dose intensities were observed for venetoclax and R-CHOP components across venetoclax exposures, suggesting venetoclax did not impact delivery of the R-CHOP backbone. Conclusions The PopPK and ER analyses, in addition to the positive benefit–risk observed in the clinical data, support the selection of 800 mg venetoclax given with R-CHOP for future studies in BCL-2-immunohistochemistry-positive patients with 1L DLBCL. Trial Registration ClinicalTrials.gov Identifier NCT02055820. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01919-z.

Prediction of human pharmacokinetics (PK) based on preclinical information for antibody–drug conjugates (ADCs) provide important insight into first‐in‐human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method to predict human PK for ADCs from animal PK data in the linear range. Different methods for projecting human clearance (CL) from animal PK data for 11 ADCs exhibiting linear PK over the tested dose ranges were examined: multiple species allometric scaling (CL vs. body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent, and scaling from only cynomolgus monkey PK data. Two analytes of interest for ADCs, namely total antibody and conjugate (measured as conjugated drug or conjugated antibody), were assessed. Percentage prediction errors (PEs) and residual sum of squares (RSS) were compared across methods. Human CL was best estimated using cynomolgus monkey PK data alone and an allometric scaling exponent of 1.0 for CL. This was consistently observed for both conjugate and total antibody analytes. Other scaling methods either underestimated or overestimated human CL, or produced larger average absolute PEs and RSS. Human concentration‐time profiles were also reasonably predicted from the cynomolgus monkey data using species‐invariant time method with a fixed exponent of 1.0 for CL and 1.0 for volume of distribution. In conclusion, results from this retrospective analysis of 11 ADCs indicate that allometric scaling of CL with an exponent of 1.0 using cynomolgus monkey PK data alone can successfully project human PK profiles of an ADC within linear range.

Purpose The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing. Methods Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance. Results No clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100–146 kg versus 38–versus versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK. Conclusions In patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100–146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.

Model-informed drug development (MIDD) has become an important approach to improving clinical trial efficiency, optimizing drug dosing, and proposing drug labeling in the absence of dedicated clinical trials. For the first time, we developed a physiologically based pharmacokinetic (PBPK) model-based approach to assess CYP3A-mediated drug-drug interaction (DDI) risk for polatuzumab vedotin (Polivy), an anti-CD79b-vc-monomethyl auristatin E (MMAE) antibody-drug conjugate (ADC). The model was developed and verified using data from the existing clinical DDI study for brentuximab vedotin, a similar vc-MMAE ADC. Analogous to the brentuximab vedotin clinical study, polatuzumab vedotin at the proposed labeled dose was predicted to have a limited drug interaction potential with strong CYP3A inhibitor and inducer. Polatuzumab vedotin was also predicted to neither inhibit nor induce CYP3A. The present work demonstrated a high-impact application using a PBPK MIDD approach to predict the CYP3A-mediated DDI to enable drug labeling in the absence of any dedicated clinical DDI study. The key considerations for the PBPK report included in the Biologics License Application/Marketing Authorization Application submission, as well as the strategy and responses to address some of the critical and challenging questions from the health authorities following the submission are also discussed. Our experience and associated perspective using a PBPK approach to ultimately enable a drug interaction label claim for polatuzumab vedotin in lieu of a dedicated clinical DDI study, as well as the interactions with the regulatory agencies, further provides confidence in applying MIDD to accelerate the registration and approval of new drug therapies.

Exposure-response relationships were investigated to assess the risk/benefit of polatuzumab vedotin (pola) + bendamustine-rituximab (pola + BR) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Analyses were conducted in pivotal study GO29365 (NCT02257567; BR/pola + BR/pola + BG [BG: bendamustine-obinutuzumab]; 1.8 mg/kg pola, every 3 weeks [Q3W], six cycles), and supportive studies DCS4968g (NCT01290549) and GO27834 (NCT01691898) (pola/pola + R/pola + G; 0.1-2.4 mg/kg pola Q3W; eight-cycle landmark), separately. Exposure was characterized as simulated cycle-6 AUC and

Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically.Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug-drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios.The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range.The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.

Minimal residual disease (MRD) is an important emerging clinical end point in chronic lymphocytic leukemia (CLL). The objective of this research was to develop an integrated mechanistic model to evaluate the impact of venetoclax-rituximab combination therapy on MRD kinetics. Using data from 435 patients with relapsed or refractory CLL, an integrated model was developed and validated that accounted for venetoclax dosing and pharmacokinetics, rituximab treatment, absolute lymphocyte count, and blood and bone marrow (BM) MRD data. Simulations of venetoclax-rituximab (six cycles) combination predicted the proportion (90% confidence interval) of patients with BM MRD below 10-4 to be 57% (54-61%) and 63% (59-67%) at 12 and 24 months of treatment, respectively. Continued venetoclax treatment to 48 months only increased the predicted rate of negative BM MRD to 66% (63-70%). These results indicate that treatment with venetoclax-rituximab combination for a finite 2-year period would nearly maximize the rate of negative BM MRD (< 10-4 ). Preliminary clinical data agree with these predictions and more long-term follow-up data are awaited to confirm the same.

To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules. Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs. In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set. For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.

Background In the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx™) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure. Objectives and methods Exposure–response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints. Results Compared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (− 11.9 vs − 9.1 and − 4.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (grade ≥ 1), fatigue/asthenia (grade ≥ 3), diarrhea (grade ≥ 3), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose. Conclusion ER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs. Electronic supplementary material The online version of this article (10.1007/s00280-018-3579-7) contains supplementary material, which is available to authorized users.

Purpose An integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations. Methods Plasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies. Results PK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40–50% lower predicted steady-state cabozantinib plasma concentrations. Conclusion This popPK analysis showed cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg cabozantinib tablet dose. Possible factors that may underlie the higher cabozantinib clearance observed in MTC patients are discussed. Electronic supplementary material The online version of this article (10.1007/s00280-018-3581-0) contains supplementary material, which is available to authorized users.

This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration. Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10–15 ms increase in delta–delta Fridericia corrected QT (∆∆QTcF) and delta–delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study. Cabozantinib treatment prolongs the ∆∆QTcF interval by 10–15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

Background: Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax–rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure–response analysis. Methods: Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure–response analysis. Results: The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21–39%). Apparent central volume of distribution was 30% lower (95% CI 22–38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes. Conclusions: The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure–response evaluation.

Exposure–response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (CmeanSS,nominal) for tolerability; exposure–safety analyses used logistic regression. Exposure–progression-free survival (PFS) relationships were assessed using MURANO data, with CmeanSS,nominal as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.

Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child–Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq®) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63–81 % or 7–30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34–38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76–77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.

Cabozantinib is a tyrosine kinase inhibitor approved in the USA and EU for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). The indicated cabozantinib dose is 140 mg/day, with dose modifications allowed for patients who develop adverse events (AEs). The analysis objective was to develop a population pharmacokinetic (PopPK) model in MTC patients and to use the model for exposure-response (ER) analysis of dose modifications. A PopPK model for cabozantinib was developed using data from three clinical trials (2079 evaluations from 289 patients), including a randomized, double-blind, placebo-controlled phase III study of patients with progressive, metastatic MTC. The PopPK model predictions [model-predicted steady-state area under the plasma concentration–time curve (AUCss,pred)] were used for an ER analysis of the time to first dose modification. The final PopPK model was a one-compartment model with first-order absorption and first-order elimination. Estimated cabozantinib apparent oral clearance (CL/F) and apparent volume of distribution (V c/F) were 106 L/day [±2.98 % relative standard error (RSE)] (males) and 349 L (±2.73 % RSE), respectively. CL/F was reduced by 22 % (to 83 L/day) in females. Sex and body mass index (BMI) were significant covariates that combined contributed 15 % to the variability in cabozantinib CL/F, but did not warrant dose adjustment. Higher cabozantinib AUCss,pred was correlated to an increased risk of early dose modification and a lower average dose through to Day 85. Early cabozantinib dose modification was not associated with a reduction in progression-free survival (PFS). A PopPK model was developed for cabozantinib pharmacokinetics in MTC patients. Higher cabozantinib exposure was associated with earlier first dose modification and a lower average administered dose through to Day 85. Early first dose modification did not appear to impact PFS.

Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0-inf , whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0-inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax , AUC0-24 , or AUC0-inf . In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.

Purpose Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. Methods This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). Results Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3–16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3–27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. Conclusions Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3283-z) contains supplementary material, which is available to authorized users.

The use of cone beam CT (CBCT) is common among dentists and dental specialists in North America and the world. The regions of interest captured by these machines vary in size and applications are numerous. If using the image data from this modality, clinicians are obligated to examine the entire volume and to understand and recognize all the anatomy in the head and neck region that can be portrayed and any abnormalities detected in otherwise normal surroundings. This article attempts to identify common entities found in the anatomic regions captured in a CBCT volume and those common abnormalities that must be referred.

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.

Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional “3+3” design. Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non–dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses. Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507–16. ©2010 AACR.

Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing (14)C-cabozantinib (100 µCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 µM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 µM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 µM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL-1644 may represent potential for drug-drug interactions.

To gain a better understanding of the mechanism of action of the metal cation–containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for the evaluation of motexafin lutetium (MLu, lutetium texaphyrin, PCI-0123) pharmacokinetics in human plasma. The LC-MS/MS method was specific for MLu, whereas the ICP-AES method measured total elemental lutetium. Both methods were fast, simple, precise, and accurate. For the LC-MS/MS method, a closely related analogue (PCI-0353) was used as the internal standard (IS). MLu and the IS were extracted from plasma by protein precipitation and injected into an LC-MS/MS system configured with a C18 column and an electrospray interface. The lower limit of quantitation was 0.05 microg MLu mL(-1), with a signal-to-noise ratio of 15:1. The response was linear from 0.05 to 5.0 microg MLu mL(-1). For the ICP-AES method, indium was used as the IS. The sample was digested with nitric acid, diluted, filtered, and then injected into the ICP-AES system. Two standard curve ranges were validated to meet the expected range of sample concentrations: 0.5 to 50, and 0.1 to 10 microg Lu mL(-1). The LC-MS/MS and ICP-AES methods were validated to establish accuracy, precision, analyte stability, and assay robustness. Interday precision and accuracy of quality control samples wereor =6.3% coefficient of variation (CV) and within 2.2% relative error (RE) for the LC-MS/MS method, andor =8.7% CV and within 4.9% RE for the ICP-AES method. Plasma samples from a subset of patients in a clinical study were analyzed using both methods. For a representative patient, over 90% of the elemental lutetium in plasma could be ascribed to intact MLu at early time points. This percentage decreased to 59% at 48 hours after dosing, suggesting that some degradation and/or metabolism of the drug may have occurred.

The use of conebeam computed tomography (CBCT) carries with it medicolegal risks of which the practitioner should be aware. These include licensing and malpractice liability concerns. A practitioner who intends to take and/or use CBCT scans should seek advice from his malpractice carrier before doing so. All scans should be read by someone competent to interpret them. Using the services of an out-of-state radiologist to read scans poses its own set of risks. Consultation with a malpractice carrier and dental boards is advisable in this situation.

Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96–7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease. Clin Cancer Res; 20(9); 2445–56. ©2014 AACR.

PURPOSE: Motexafin gadolinium is a magnetic resonance imaging (MRI)–detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival. PATIENTS AND METHODS: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range. RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium’s tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%. CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.

Background Sapphyrin analogues and related porphyrin-like species have attracted attention as anticancer agents due to their selective localization in various cancers, including hematologic malignancies, relative to surrounding tissues. Sapphyrins are electron affinic compounds that generate high yields of singlet oxygen formation. Although initially explored in the context of photodynamic therapy, sapphyrins have intrinsic anticancer activity that is independent of their photosensitizing properties. However, the mechanisms for their anticancer activity have not been fully elucidated. Results We have prepared a series of hydrophilic sapphyrins and evaluated their effect on proliferation, uptake, and cell death in adherent human lung (A549) and prostate (PC3) cancer cell lines and in an A549 xenograft tumor model. PCI-2050, the sapphyrin derivative with the highest in vitro growth inhibitory activity, significantly lowered 5-bromo-2'-deoxyuridine incorporation in S-phase A549 cells by 60% within eight hours and increased levels of reactive oxygen species within four hours. The growth inhibition pattern of PCI-2050 in the National Cancer Institute 60 cell line screen correlated most closely using the COMPARE algorithm with known transcriptional or translational inhibitors. Gene expression analyses conducted on A549 plateau phase cultures treated with PCI-2050 uncovered wide-spread decreases in mRNA levels, which especially affected short-lived transcripts. Intriguingly, PCI-2050 increased the levels of transcripts involved in RNA processing and trafficking, transcriptional regulation, and chromatin remodeling. We propose that these changes reflect the activation of cellular processes aimed at countering the observed wide-spread reductions in transcript levels. In our A549 xenograft model, the two lead compounds, PCI-2050 and PCI-2022, showed similar tumor distributions despite differences in plasma and kidney level profiles. This provides a possible explanation for the better tolerance of PCI-2022 relative to PCI-2050. Conclusion Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression.

Liquid chromatography-fluorescence (LC-FLS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) methods were developed and validated for the evaluation of motexafin gadolinium (MGd, Xcytrin) pharmacokinetics and biodistribution in plasma and tissues. The LC-FLS method exhibited the greatest sensitivity (0.0057 microg mL(-1)), and was used for pharmacokinetic, biodistribution, and protein binding studies with small sample sizes or low MGd concentrations. The LC-MS/MS method, which exhibited a short run time and excellent selectivity, was used for routine clinical plasma sample analysis. The ICP-MS method, which measured total Gd, was used in conjunction with LC methods to assess MGd stability in plasma. All three methods were validated using human plasma. The LC-FLS method was also validated using plasma, liver and kidneys from mice and rats. All three methods were shown to be accurate, precise and robust for each matrix validated. For three mice, the mean (standard deviation) concentration of MGd in plasma/tissues taken 5 hr after dosing with 23 mg kg(-1) MGd was determined by LC-FLS as follows: plasma (0.025+/-0.002 microg mL(-1)), liver (2.89+/-0.45 microg g(-1)), and kidney (6.09+/-1.05 microg g(-1)). Plasma samples from a subset of patients with brain metastases from extracranial tumors were analyzed using both LC-MS/MS and ICP-MS methods. For a representative patient,or = 90% of the total Gd in plasma was accounted for as MGd over the first hour post dosing. By 24 hr post dosing, 63% of total Gd was accounted for as MGd, indicating some metabolism of MGd.

Conjugates between methotrexate (MTX, Matrex®, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid), an antifolate cancer chemotherapeutic to which resistance is often observed, and motexafin gadolinium (MGd), an experimental agent demonstrating selective tumor localization, are described. These systems were prepared in order to test whether linking these two species would produce agents with enhanced activity relative to MTX alone. Both ester- and amide-linked conjugates were synthesized starting from MGd and MTX. The ester conjugate showed greater in vitro anti-proliferative activity against the A549 lung carcinoma cell line at short incubation times than did MTX alone. Neither the amide conjugate, nor MGd, showed any observable activity under these in vitro conditions. These results are rationalized in terms of enhanced cellular uptake of both the ester and amide conjugates that is coupled with an effective rate of release (e.g., inherent or enzyme-mediated hydrolysis) in the case of the ester-linked conjugate, but not the corresponding amide system.

The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.