A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment.

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on Cmax and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI.

Modulation of Fexofenadine Pharmacokinetics by Osimertinib in Patients With Advanced EGFR-Mutated Non-Small Cell Lung Cancer.

Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration-time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4-78.6) and 76% (90%CI, 49.3-108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2-45.8) and 25% (90%CI, 5.6-48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor.

Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin.

AIM: We report on two Phase 1, open-label, single-arm studies assessing the effect of osimertinib on simvastatin (CYP3A substrate) and rosuvastatin (breast cancer resistance protein substrate [BCRP] substrate) exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer who have progressed after treatment with an EGFR tyrosine kinase inhibitor, to determine, upon coadministration, whether osimertinib could affect the exposure of these agents. METHODS: Fifty-two patients in the CYP3A study (pharmacokinetic [PK] analysis, n = 49), and 44 patients in the BCRP study were dosed (PK analysis, n = 44). In the CYP3A study, patients received single doses of simvastatin 40 mg on Days 1 and 31, and osimertinib 80 mg once daily on Days 3-32. In the BCRP study, single doses of rosuvastatin 20 mg were given on Days 1 and 32, and osimertinib 80 mg once daily on Days 4-34. RESULTS: Geometric least squares mean (GLSM) ratios (90% confidence intervals) of simvastatin plus osimertinib for area under the plasma concentration-time curves from zero to infinity (AUC) were 91% (77-108): entirely contained within the predefined no relevant effect limits, and Cmax of 77% (63, 94) which was not contained within the limits. GLSM ratios of rosuvastatin plus osimertinib for AUC were 135% (115-157) and Cmax were 172 (146, 203): outside the no relevant effect limits. CONCLUSIONS: Osimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.

Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects.

The aims of this randomized, double-blind, three-arm, single-dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as "M923") to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration (Cmax ), area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf ), and AUC from time 0 to 336 hours (AUC0-336 ). Secondary endpoints included safety and immunogenicity assessments. Healthy subjects were randomized 1:1:1 to receive a 40-mg dose of M923 (n = 107); adalimumab US Humira (n = 105), hereafter referred to as "US Humira"; or adalimumab EU Humira (n = 103), hereafter referred to as "EU Humira." PK equivalence was demonstrated for all primary PK endpoints. Geometric least squares means ratios (GMRs) for Cmax , AUC0-inf , and AUC0-336 were 99.4, 100.9, and 100.5, respectively, between the M923 and EU Humira arms and 102.6, 104.2, and 102.9 between the M923 and US Humira arms. The 90% confidence intervals of the GMRs for all PK endpoints were within prespecified confidence bounds of 80%-125%. Adverse event rates were similar across the M923 (47.7%), US Humira (50.9%), and EU Humira (53.3%) arms and were generally mild (73.7%) or moderate (22.0%). The proportion of subjects with a confirmed antidrug antibody (ADA) response was similar across study arms. This study demonstrated bioequivalent PK among M923, US Humira, and EU Humira and demonstrated that the PK parameters were consistent with similar safety and tolerability profile and ADA response rates.

The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib.

AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two Phase I, open-label, two-part clinical studies. Part one of both studies is reported. METHODS: In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6-18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80 mg once daily on Days 1-77 and rifampicin 600 mg once daily on Days 29-49. RESULTS: In the itraconazole study (n = 36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for Cmax and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no-effect upper limit of 200%. In the rifampicin study (n = 40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for Css,max and AUCτ were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib Css,max and AUCτ values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. CONCLUSIONS: Osimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.

The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers.

Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1-4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least-squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least-squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration-time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733.

Pharmacokinetics and Pharmacodynamics of the Nonvitamin K Antagonist Oral Anticoagulant Edoxaban When Administered Alone or After Switching from Rivaroxaban or Dabigatran Etexilate in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Edoxaban is an oral, once-daily direct factor Xa inhibitor. To support the possibility that patients may choose to switch treatment from another nonvitamin K antagonist oral anticoagulant to edoxaban, this clinical study was conducted to evaluate the pharmacokinetic and pharmacodynamic effects of edoxaban after switching from rivaroxaban or dabigatran etexilate to edoxaban. METHODS: In this open-label, three-period, crossover study, healthy subjects received 3 days of edoxaban 60 mg daily, rivaroxaban 20 mg daily, or dabigatran etexilate 150 mg twice daily, followed by edoxaban 60 mg on day 4. RESULTS: Day 4 edoxaban pharmacokinetic parameters were similar for all treatments. The peak effect of edoxaban on prothrombin time (PT) after 4 days of edoxaban only was 21.8 ± 2.46 s; after switching from rivaroxaban to edoxaban, peak effect on PT was similar at 21.8 ± 2.88 s. After switching from dabigatran etexilate to edoxaban, least squares mean activated partial thromboplastin time (aPTT) at 2 h after administration was 47.6 vs 35.0 s for edoxaban alone. The treatment difference was 12.8 s (95% confidence interval 10.5-15.1; p < 0.0001). Post hoc analysis revealed that predose aPTT was elevated on day 3 of dabigatran etexilate administration, and on day 4, indicating a carryover effect from dabigatran. All treatments were well tolerated and there were no safety concerns upon switching, with no increased risk of bleeding. CONCLUSIONS: The study results suggest that switching to edoxaban from either rivaroxaban or dabigatran etexilate at the time of the next dose is well tolerated and maintains coagulation status.

Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers.

The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.

Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships.

BACKGROUND: There have been no published reports comparing the CYP450 GeneChip microarray assay with more standard methods of genetic testing. METHODS: We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay. Five of the CYP2D6 alleles (*3, *4, *6, *7, and *9) were tested by both AS-PCR and the CYP450 GeneChip assay in an independent and blinded fashion in 232 of the 236 healthy volunteers. The combined CYP2D6 genotype from both methods was used to divide the population into four subgroups, poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs), based on their relative function and ability to express the CYP2D6 gene. The urinary elimination of dextromethorphan was assessed in each of these CYP2D6 subgroups. RESULTS: The CYP2D6*3, *4, *6, *7, and *9 alleles showed a high degree of concordance between the CYP450 GeneChip and AS-PCR methods (>99% concordance). The mean (SD) of the log[dextromethorphan metabolic ratio (MR)] in the four CYP2D6 subgroups was PM = 0.49 (0.38); IM = -1.24 (0.53); EM = -2.35 (0.61); and UM = -2.43 (0.38). CONCLUSIONS: Oligonucleotide microarray technology is an efficient and reliable way to test for CYP2D6 gene variation based on five alleles compared by separate methods. The methodology is influenced by the quality and amount of DNA present. The log(dextromethorphan MR) is a highly variable index that appears to reflect the crude nature of the dextromethorphan MR as an indicator of CYP2D6 in vivo enzyme activity.