BackgroundStatins are effective agents in the primary and secondary prevention of cardiovascular disease, but treatment response to statins varies among individuals. We analyzed multiple genetic polymorphisms and assessed pharmacokinetic and lipid-lowering responses after atorvastatin 80 mg treatment in healthy Korean individuals.MethodsAtorvastatin 80 mg was given to 50 healthy Korean male volunteers. Blood samples were collected to measure plasma atorvastatin and lipid concentrations up to 48 hours after atorvastatin administration. Subjects were genotyped for 1,936 drug metabolism and transporter genetic polymorphisms using the Affymetrix DMET plus array.ResultsThe pharmacokinetics and lipid-lowering effect of atorvastatin showed remarkable interindividual variation. Three polymorphisms in the SLCO1B1, SLCO1B3, and ABCC2 genes were associated with either the maximum concentration (Cmax) of atorvastatin or changes in total cholesterol or low-density lipoprotein cholesterol (LDL-C). Minor homozygotes (76.5 ng/mL) of SLCO1B1 c.-910G>A showed higher Cmax than heterozygotes (34.0 ng/mL) and major homozygotes (33.5 ng/mL, false discovery rate P=0.040). Cmax and the area under the plasma concentration curve from hour 0 to infinity (AUC∞) were higher in carriers of the SLCO1B1*17 haplotype that included c.-910G>A than in noncarriers (46.1 vs 32.8 ng/mL for Cmax; 221.5 vs 154.2 ng/mL for AUC∞). SLCO1B3 c.334G>T homozygotes (63.0 ng/mL) also showed higher Cmax than heterozygotes (34.7 ng/mL) and major homozygotes (31.4 ng/mL, FDR P=0.037). A nonsynonymous ABCC2 c.1249G>A was associated with small total cholesterol and LDL-C responses (0.23% and −0.70% for G/A vs −11.9% and −17.4% for G/G). The Cmax tended to increase according to the increase in the number of minor allele of SLCO1B1 c. −910G>A and SLCO1B3 c.334G>T.ConclusionGenetic polymorphisms in transporter genes, including SLCO1B1, SLCO1B3, and ABCC2, may influence the pharmacokinetics and lipid-lowering response to atorvastatin administration.

3000 Background: Belvarafenib (HM95573/GDC-5573) is an oral type II pan-RAF kinase inhibitor which demonstrates selective anti-tumor activity in several non-clinical cancer models and in cancer patients with RAS- or RAF- mutation. Here we present overall safety and efficacy findings of two phase 1 studies, consisting of dose escalation and dose expansion stages. Methods: Patients with advanced solid cancers harboring documented RAS- or RAF- mutation were enrolled. In the dose escalation study, patients were treated with Belvarafenib at a starting dose of 50 mg once daily (QD) to 800 mg BID to assess safety and tolerability and identify the recommended dose (RD). Dose escalation was guided based on pharmacokinetic data and used a traditional 3+3 design. The dose expansion study was comprised of 6 cohorts (according to the type of tumor and RAS- or RAF gene mutation) and patients received the RD of Belvarafenib. The primary objective was to explore anti-tumor activity (per RECIST 1.1) and pharmacodynamic effects. Results: The dose escalation study included 72 patients in 9 dose cohorts (cut-off date of 18 Jan 2017). Dose dependent increase in exposures observed up to 650 mg BID. The most common treatment-emergent adverse events that occurred in more than 20% of patients were rash, dermatitis acneiform and pyrexia. A total of 4 DLTs (different kinds of rashes) were reported and included 2 DLTs at the 800 mg BID level. Therefore, 650 mg BID was considered the MTD and 450 mg BID was identified as the RD for Belvarafenib. There were 7 partial responses (3 confirmed PRs) from 200 mg QD to 800 mg BID in NRAS-mutant melanoma, BRAF-mutant melanoma, KRAS-mutant sarcoma, and BRAF-mutant GIST. Four of nine patients with NRAS-mutant melanoma had a PR (ORR 44%). The dose expansion study included 63 patients in 5 indication-specific and basket cohorts administered with 450 mg BID Belvarafenib (cut-off date of 6 Oct 2018). No new safety signal was detected. There were two PRs each in patients with NRAS-mutant melanoma (2/9), BRAF-mutant melanoma (2/6) and BRAF-mutant CRC (2/7), respectively. Conclusions: Belvarafenib was well tolerated and exhibited anti-tumor activity in patients with advanced solid tumors harboring RAS or RAF mutations. Belvarafenib is being further investigated in combination with the MEK inhibitor cobimetinib. Clinical trial information: NCT02405065, NCT03118817.

The main objective of this phase I trial was to investigate pharmacokinetics (PKs) of olmutinib in three racial subjects. We also evaluate safety/tolerability and a population PK and pharmacogenomic analysis were performed for explorative purposes. A dose escalation study was conducted in 56 Korean, Japanese and Caucasian subjects. The food effect was assessed in the 300 mg Korean group. Individual PK parameters were calculated by non‐compartmental methods and presented by dose and race. Genotype analysis was performed using DMET® plus to identify genotypes which affect PK characteristics. A population PK model was developed to explore inter‐individual variability and to evaluate the influence of possible covariates using NONMEM®. Tmax was 2‐3 hour, regardless of race. The mean terminal half‐life ranged from 4.8 to 7.4 hour, with no significant differences between dose or racial groups. Dose‐normalized Cmax and AUClast were not significantly different between race groups. PK parameters were similar between the fasting and fed conditions. A single‐nucleotide polymorphism in the GSTM3 gene (rs4783) and a copy number variation in the GSTM1 gene were significantly related to AUC. A one‐compartment model with first‐order absorption adequately described the observed olmutinib data. Thirty adverse events were observed in 15 subjects, of which 26 events, all mild, were possibly related to olmutinib. A single oral dose of olmutinib 100‐300 mg was safe and well tolerated. PK parameters were dose‐proportional and did not differ by race. Food intake did not affect olmutinib absorption. Pharmacogenomic analysis indicated that glutathione S‐transferase might be involved in olmutinib metabolism.