Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers.

Apararenone is a long-acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single- and multiple-dose apararenone were assessed in 3 phase 1 randomized, double-blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single-dose apararenone (3.75-640 mg) and multiple-dose apararenone (10-40 mg/day on days 1-14, 320 mg loading dose on day 1 + 10 mg/day on days 2-14, or 40-320 mg loading dose on day 1 + 2.5-20 mg/day on days 2-14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single-dose apararenone (5-320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single-dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose-proportional increase was observed in PK parameters over the apararenone dose range of 3.75-40 mg; at higher doses, a less than dose-proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half-life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.

Drug-Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone With Midazolam, Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers.

PURPOSE: To characterize the clinical relevance of in vitro drug-drug interaction findings with apararenone (MT-3995), the effects of apararenone on the sensitive substrates of cytochrome P450 3A4 (midazolam) and 2C9 (warfarin), and P-glycoprotein (digoxin), were assessed through a series of studies conducted in healthy volunteers. METHODS: Three studies were conducted in 56 healthy adults. Study 1 investigated the effects of the administration of apararenone with midazolam; apararenone was administered on days 2 (320 mg) and days 3-15 (20 mg/d), and midazolam 2 mg, on days 1 and 15. Study 2 investigated the effects of the administration of apararenone with warfarin; apararenone was administered on days 8-11 (40 mg/d) and days 12-27 (10 mg/d), and warfarin 25 mg, on days 1 and 21. Study 3 assessed the effects of the administration of apararenone with digoxin; apararenone was administered on days 11 (160 mg) and days 12-28 (10 mg/d), and digoxin 0.5 mg, on days 1 and 24. Pharmacokinetic parameters included Cmax, AUC0-t, and AUC0-∞. The safety profile was evaluated based on adverse events from spontaneous reports and clinical findings. FINDINGS: After the administration of midazolam together with apararenone, compared with midazolam alone, the midazolam ± apararenone treatment ratios (90% CIs) of the geometric least squares (LS) mean Cmax, AUC0-t, and AUC0-∞ values were 1.263 (1.147-1.392), 1.342 (1.220-1.477), and 1.370 (1.225-1.534), respectively. After the administration of warfarin ± apararenone, the R-warfarin ± apararenone treatment ratios (90% CIs) of the geometric LS mean Cmax, AUC0-t, and AUC0-∞ values were 1.008 (0.934-1.089), 1.078 (1.029-1.129), and 1.110 (1.056-1.166). Corresponding values for S-warfarin were 1.025 (0.941-1.117), 1.024 (0.979-1.071), and 1.031 (0.984-1.080). After the administration of digoxin ± apararenone, the digoxin ± apararenone treatment ratios (90% CIs) of the geometric LS mean Cmax, AUC0-t, and AUC0-∞ values were 0.929 (0.789-1.093), 0.894 (0.797-1.033), and 0.887 (0.805-0.977), respectively. Treatment-emergent adverse events were generally of mild to moderate intensity, and no serious adverse events of any kind were reported. IMPLICATIONS: The findings from this analysis of data from healthy volunteers suggest minimal risk for potential drug-drug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568.

Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment).

PURPOSE: Cariprazine is a potent dopamine D3-preferring D3/D2 receptor partial agonist in development for the treatment of schizophrenia, bipolar mania, and depression. Pharmacokinetics of cariprazine and the two clinically relevant metabolites (desmethyl- and didesmethyl-cariprazine) was evaluated in a clinical pharmacology study. METHODS: This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (≤4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. RESULTS: Steady state was reached within 1-2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased ~50% at 1 week, and total active moieties decreased ~90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was ~1 week. Incidence of treatment-emergent adverse events was 97.4%; 15.8% of patients discontinued due to adverse events. No abnormal laboratory values or major differences from baseline in extrapyramidal symptoms were observed. CONCLUSION: Cariprazine and its active metabolites reached steady state within 4 weeks, and exposure was dose proportional over the range of 3-9 mg/day. Once-daily cariprazine was generally well tolerated in adult patients with schizophrenia.

Genetic deficiency of carnitine/organic cation transporter 2 (slc22a5) is associated with altered tissue distribution of its substrate pyrilamine in mice.

Carnitine/organic cation transporter 2 (OCTN2) recognizes various cationic compounds as substrates in vitro, but information on its pharmacokinetic role in vivo is quite limited. This paper demonstrates altered tissue distribution of the OCTN2 substrate pyrilamine in juvenile visceral steatosis (jvs) mice, which have a hereditary defect of the octn2 gene. At 30 min after intravenous injection of pyrilamine, the tissue-to-plasma concentration ratio (K(p)) in the heart and pancreas was higher, whereas the K(p) in kidney and testis was lower in jvs mice compared with wild-type mice. Pyrilamine transport studies in isolated heart slices confirmed higher accumulation, together with lower efflux, of pyrilamine in the heart of jvs mice. The higher accumulation in heart slices of jvs mice was abolished by lowering the temperature, by increasing the substrate concentration, and in the presence of other H(1) antagonists or another OCTN2 substrate, carnitine, suggesting that OCTN2 extrudes pyrilamine from heart tissue. On the other hand, the lower distribution to the kidney of jvs mice was probably due to down-regulation of a basolateral transporter coupled with OCTN2, because, in jvs mice, (i) the K(p) of pyrilamine in kidney assessed immediately after intravenous injection (approximately 1 min) was also lower, (ii) the urinary excretion of pyrilamine was lower, and (iii) the uptake of pyrilamine in kidney slices was lower. The renal uptake of pyrilamine was saturable (K(m) approximately 236 microM) and was strongly inhibited by cyproheptadine, astemizole, ebastine and terfenadine. The present study thus indicates that genetic deficiency of octn2 alters pyrilamine disposition tissue-dependently.