Association of cabozantinib residual concentration (Ctrough) and blood clearance (Cl/F) with toxicity (tox) and progressive disease (PD) in metastatic renal cell carcinoma (mRCC) patients (pts): Results from a monocentric pharmacokinetics (PK) study.

292 Background: Cabozantinib is a TKI with a substantial efficacy in mRCC. It is associated with a relevant tox leading frequent dose modifications (DM) or drug discontinuations (DD). While an exposure/safety relation has been demonstrated for this drug, an exposure/efficacy relation is still unknown. Cl/F is a measure of elimination of a drug from blood or plasma and lower Cl/F of cabozantinib has been previously associated with increased DM rate in mRCC. Methods: We performed a monocentric PK (INDS MR 5612140520) study in patients with mRCC. Blood draw for assessment of cabozantinib PK was performed at least 8 hours from the last drug dose. Ctrough was estimated with the following equation: Ctrough=Cmeas*0,5DI-24/t1/2. Ctrough and Cl/F were compared in patients with or without a relevant tox and in PD pts vs SD/PR pts. Relevant tox was defined either as G3-4 tox or G2 tox leading to DM or DD. Differences in Ctrough and CL were assessed between the groups with Mann Withney U test. Results: From 01.10.19 to 31.08.20 66 pts were included in this analysis. Twenty one relevant tox and 29 PD were observed. Ctrough was higher in pts experiencing relevant tox than in those who did not: 624,6 ng/ml (IQR 494-1030,2 ng/ml) vs 505,2 ng/ml (IQR 329,2-910,2), p0.012. Conversely Cl/F was lower in relevant tox vs not tox1,85 l/h (IQR 1,4-2,2 l/h) vs 2.27 l/h (IQR 1,7-3,2), p 0.024. In PD pts, Ctrough was lower than in SD/PR pts: 419ng/ml (IQR 317,2 -549,1 ng/ml) vs 554 ng/ml (IQR 416,9-795,6), p 0.0105, while Cl/F was higher in PD patients: 2,6 l/h (IQR 2,14-3,44 l/h) vs SD/PR patients 1.9 l/h (1,930 l/h;IQR 1,35-2,53 l/h); p= 0.011. Time from day cycle 1 to PK blood draw was significatively longer in non-tox pts and numerically longer in PD pts, which have the lowest Ctrough and the highest Cl/F. Conclusions: Cabozantinib toxicity is associated to a higher Ctrough and a lower Cl/F. Cabozantinib PD is associated to a lower Ctrough and a higher Cl/F. Cl/F should be assessed alongside with Ctrough in Cabozantinib PK blood test; Ctrough may decrease and conversely Cl/F may increase with time on treatment. [Table: see text]

Voriconazole Autoinduction and Saturable Metabolism After Cessation of Rifampin in a Patient With Invasive Central Nervous System Aspergillus: Importance of Therapeutic Drug Monitoring

Purpose: Optimization of antifungal therapy with voriconazole can be challenging due to inter- and intrapatient variability in voriconazole pharmacokinetics (PK). In this case, we introduce challenges in voriconazole therapy due to drug–drug interactions, autoinduction, and saturable metabolism. Summary: A 32-year-old male on chronic prednisone developed central nervous system (CNS) aspergillosis. He was started on high-dose intravenous (IV) voriconazole 8.5 mg/kg every 12 hours due to concerns for lasting induction effects of recent rifampin therapy. The initial voriconazole trough was 2 μg/mL. Frequent dose adjustments were made to maintain the therapeutic trough goal. On day 24 of voriconazole therapy, his trough was undetectable on IV voriconazole 5.5 mg/kg every 12 hours. His dose was escalated to 8.5 mg/kg every 12 hours to avoid subtherapeutic levels and therapeutic failure. On day 48, his trough level was 1.1 μg/mL on the same dose. His regimen was changed to 6.5 mg/kg every 8 hours at this point. Sixteen days after this regimen on day 74 of voriconazole therapy, his trough was 27.2 μg/mL indicating saturable PK of voriconazole in the absence of interacting drugs. Conclusion: Our findings highlight the unpredictable PK of voriconazole and reinforce the importance of continuous therapeutic drug monitoring in critically ill patients.

Long-Acting Injectable Antipsychotic Medications in Schizophrenia Management

Antipsychotic medications are indicated for the treatment of schizophrenia and other psychiatric disorders including bipolar disorder. However, oral antipsychotics are associated with a number of issues including poor treatment adherence. Long Acting Injectable (LAI) antipsychotics were designed to address these issues with oral antipsychotics. LAI antipsychotics offer several advantages including less frequent dose administration, better adherence and tolerability, and relapse prevention, which in turn help in improving patients’ quality of life. Recent development of atypical antipsychotics has the advantages over typical antipsychotics in terms of improved efficacy and tolerability. This review highlights the advantages and disadvantages of LAI antipsychotics, outlines the currently available LAIs and their indications, and real-world evidence for LAIs based on the observational st

Association between clinical response and toxicities with drug exposure in an alternative dosing regimen of sunitinib.

439 Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients initiating AD sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and plasma steady-state levels (Cmax) were quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Results: 36 patients with a mean age of 59.1 ± 10.1 years were recruited. Majority were males (81%) and Chinese (86%). Among the 24 and 16 analyzable cases for cycle 1 and 2, median total Cmax were 0.088 and 0.094 µg/ml respectively. Sixteen patients completed 2 treatment cycles; 7 (44%) partial response, 5 (31%) stable disease and 4 (25%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical response and among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]

Phase Ib/II trial of gemcitabine, cisplatin, plus lenalidomide as first-line therapy for patients with metastatic urothelial carcinoma.

321 Background: Cisplatin-based chemotherapy is standard in patients (pts) with metastatic urothelial carcinoma (MUC), though outcomes remain poor and novel approaches are needed. Lenalidomide, a potent thalidomide analog with antiangiogenic and immunomodulatory properties, has been shown to enhance the antiproliferative properties of standard chemotherapy in nonclinical studies of urothelial cancer (Apolo, ASCO 2011). In this phase Ib/II clinical trial we aimed to determine the safety and efficacy of gemcitabine, cisplatin, plus lenalidomide (GCL) in pts with MUC. Methods: Pts with chemotherapy-naïve MUC received gemcitabine 1000mg/m2 days 1 and 8 and cisplatin 70mg/m2 day 1, of a 21-day cycle. In the phase Ib portion, the dose of lenalidomide was to be dose escalated in successive cohorts starting at 10 mg PO daily, on days 1-14, using standard “3+3” dose escalation rules. The primary objective of the phase II portion was to determine the progression-free survival at one year. Results: A total of 7 pts received GCL (lenalidomide 10 mg dose level) in the phase 1b portion. A single pt experienced a dose limiting toxicity (DLT), grade 4 neutropenia. A decision was made to not dose escalate lenalidomide further due to the frequent need for dose delays and reductions of GC due to cytopenias. An additional 2 pts were enrolled in the phase II portion but the study was terminated due to frequent dose delays/reductions and slow accrual. Among the 9 pts enrolled, 5 required dose reductions of G (4 requiring >1), 4 required dose reductions of C (1 requiring >1), and 6 required at least one dose delay. The most frequent grade ≥ 3 adverse events were: neutropenia (n=7), anemia (n=3), thrombocytopenia (n=3), and diarrhea (n=2). Tumor responses included: partial response (n=3), stable disease (n=3), progressive disease (n=2), and unevaluable (n=1). Conclusions: Chronic administration of the combination of GCL was compromised by overlapping myelosuppression and the need for frequent dose reductions/delays of GC due to cytopenias. Despite promising nonclinical data, combining cytotoxic chemotherapy with “targeted” small molecules faces practical challenges. Clinical trial information: NCT01342172.

Association of drug exposure with clinical response and toxicities in metastatic renal cell carcinoma patients (mRCC) receiving an alternative dosing (AD) regimen of sunitinib.

e13582 Background: An AD regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for mRCC. This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients starting on sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and graded according to CTCAE and plasma AUCss was quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Statistical tests such as Mann-Whitney U were used to compare the levels between groups. Results: 24 patients with a mean age of 58.8 ± 11.2 years were recruited. Majority were males (75%) and Chinese (87.5%). Among the 17 and 14 analyzable cases for cycle 1 and 2, median total AUCsswere 2.2 and 2.1 µg•h/ml respectively. Fourteen patients completed 2 treatment cycles; 7 (50%) partial response, 4 (28.6%)stable disease and 3 (21.4%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical responseand among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]

Phase II trial of sorafenib (S) and vinorelbine (V) in metastatic breast cancer (mBC) with pharmacokinetics (PK) analysis.

1099 Background: S inhibits pathways involved in cancer resistance to treatments (Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability and efficacy of full doses of S and V in mBC. Toxicity data were previously reported: frequent dose reductions were noted, for which we investigated a possible PK interaction. Indeed, the metabolism of both S and V depends on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RECIST), HER2 negative mBC received first-line therapy with V (30 mg/m2 days 1, 8 every 21) + S (400 mg bid). After 8 cycles patients could be switched to S alone. For PK analysis 6 patients started S on day 4 of cycle 1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S) when V and S were administered apart from each other versus concomitantly. Plasma samples were collected at time 0 (oral intake of S or right before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7, 24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S+M2; cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS assays. Results: 27 patients (median age 57, 35-71) received a median of 8 cycles (1-28), with one patient still on treatment. With repeated cycles 48% of patients required at least 1 dose reduction and 3 patients discontinued therapy for toxicity. 30% of patients had a partial response, 85% had clinical benefit (including stable disease ≥ 4 cycles). Median progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels of V were influenced by S, with a mean Cmax right after the infusion of 1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL with concomitant S (cycle 2 day 1; paired t-test, p=0.004). Plasma levels of S and M2 showed a greater degree of interpatient variability, with no significant difference observed in the presence or absence of concomitant V. Conclusions: Combining S with V at full doses is feasible, but not devoid of toxicity. A PK interaction may contribute to the frequent dose reductions. A reasonable option in clinical practice is to start therapy at lower doses of both agents, with a gradual dose increase if well tolerated. Promising efficacy of this combination is documented, with a very high rate of disease control.