Bioequivalence Between a New Omalizumab Prefilled Syringe With an Autoinjector or with a Needle Safety Device Compared with the Current Prefilled Syringe: A Randomized Controlled Trial in Healthy Volunteers.

Omalizumab is an anti-IgE monoclonal antibody currently approved for the treatment of asthma, nasal polyps/chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria. Omalizumab is available as an injection in a prefilled syringe (PFS) with a needle safety device (NSD). New product configurations were developed to reduce the number of injections per dose administration, improve patient convenience and treatment compliance. The objective of this randomized open-label 12-week study was to demonstrate pharmacokinetic bioequivalence between (1) new PFS with autoinjector (PFS-AI), (2) new PFS-NSD configuration, and (3) current PFS-NSD configuration. Each new configuration was considered bioequivalent to the current configuration if the confidence intervals (CIs) for the geometric mean ratios (GMR) were contained in the 0.80-1.25 range for maximum concentration (Cmax), area under the concentration-time curve until the last quantifiable measurement (AUClast), and AUC extrapolated to infinity (AUCinf). Safety was assessed throughout the study. In total, 193 healthy volunteers were randomized at 1:1:1 ratio to omalizumab 1×300 mg/2 mL via new PFS-AI (n = 66), omalizumab 1×300 mg/2 mL via new PFS-NSD (n = 64), or omalizumab 2×150 mg/1 mL via current PFS-NSD (n = 63). Comparing new PFS-AI versus current PFS-NSD, the GMRs were: Cmax, 1.085; AUClast, 1.093; AUCinf, 1.100. Comparing new PFS-NSD versus current PFS-NSD, the GMRs were: Cmax, 1.006; AUClast, 1.016; AUCinf, 1.027. The 95% CIs for all GMR parameters were contained within the 0.80-1.25 range. Safety findings were consistent with the known safety profile of omalizumab. Single-dose omalizumab administered as the new PFS-AI or new PFS-NSD was bioequivalent to the current PFS-NSD.

Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and -5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean Cmax was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers.

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUClast ), and extrapolated to infinity (AUCinf ), and the maximum plasma concentration (Cmax ) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUCinf , Cmax , and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings.

Effects of triclabendazole and its metabolite exposure on the heart-rate-corrected QT intervals: A randomized, placebo- and positive-controlled thorough QT study in healthy individuals.

Triclabendazole is an effective and well-tolerated treatment for human fascioliasis. A placebo- and positive-controlled, four-sequence by four-period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two-sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3-, 4-, and 6-h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment-emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

Pharmacokinetics of Asciminib When Taken With Imatinib or With Food.

Asciminib, a first-in-class, Specifically Targeting the Abelson kinase Myristoyl Pocket (STAMP) inhibitor with the potential to overcome resistance to adenosine triphosphate-competitive tyrosine kinase inhibitors, is being investigated in leukemia as monotherapy and in combination with tyrosine kinase inhibitors including imatinib. This phase 1 study in healthy volunteers assessed the pharmacokinetics of asciminib (40 mg single dose) under 2 conditions: when taken with imatinib (steady state; 400 mg once daily) and a low-fat meal (according to imatinib prescription information), or when taken as single-agent under different food conditions. Asciminib plus imatinib with a low-fat meal increased asciminib area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (geometric mean ratios [90% confidence interval], 2.08 [1.93-2.24] and 1.59 [1.45-1.75], respectively) compared with asciminib alone under the same food conditions. Asciminib plus food decreased asciminib area under the plasma concentration-time curve from time 0 to infinity compared with asciminib taken under fasted conditions (geometric mean ratios: low-fat meal, 0.7 [0.631-0.776]; high-fat meal, 0.377 [0.341-0.417]). Asciminib plus imatinib was well tolerated with no new safety signals. Overall, coadministration of asciminib with imatinib and a low-fat meal results in a moderate increase in asciminib exposure compared with asciminib alone under the same food condition. Food itself decreases asciminib exposure, indicating that single-agent asciminib should be administered in the fasted state to prevent potential suboptimal exposures.

Pharmacokinetics of Asciminib in Individuals With Hepatic or Renal Impairment.

Asciminib is an investigational, first-in-class, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor of BCR-ABL1 with a new mechanism of action compared with approved ATP-competitive tyrosine kinase inhibitors. This report describes the findings from 2 phase 1 studies assessing the pharmacokinetic (PK) profile of a single dose of asciminib (40 mg) in individuals with impaired renal function (based on absolute glomerular filtration rate; NCT03605277) or impaired hepatic function (based on Child-Pugh classification; NCT02857868). Individuals with severe renal impairment exhibited 49%-56% higher exposure (area under the curve [AUC]), with similar maximum plasma concentration (Cmax ), than matched healthy controls. Based on these findings, as per the protocol, the PK of asciminib in individuals with mild or moderate renal impairment was not assessed. In individuals with mild and severe hepatic impairment, asciminib AUC was 21%-22% and 55%-66% higher, respectively, and Cmax was 26% and 29% higher, respectively, compared with individuals with normal hepatic function. Individuals with moderate hepatic impairment had similar asciminib AUC and Cmax than matched healthy controls. The increase in asciminib AUC and Cmax in the mild hepatic impairment cohort was mainly driven by 1 participant with particularly high exposure. Asciminib was generally well tolerated, and the safety data were consistent with its known safety profile. In summary, these findings indicate that renal or hepatic impairment has no clinically meaningful effect on the exposure or safety profile of asciminib, and support its use in patients with varying degrees of renal or hepatic dysfunction.

Pharmacokinetic drug-drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus.

Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.53- and 1.79-fold increases in steady-state metformin Cmax and AUCtau , respectively; co-administration of ranolazine 500 mg BID with metformin 1000 mg BID resulted in 1.22- and 1.37-fold increases in steady-state metformin Cmax and AUCtau , respectively. Co-administration of ranolazine and metformin was well tolerated in these T2DM subjects, with no serious adverse events or drug-related adverse events leading to discontinuation. The most common adverse events were nausea, diarrhea, and dizziness. These findings are consistent with a dose-related interaction between ranolazine and metformin, and suggest that a dose adjustment of metformin may not be required with ranolazine 500 mg BID; whereas, the metformin dose should not exceed 1700 mg of total daily dose when using ranolazine 1000 mg BID.

Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients.

Cyclosporine exhibits pharmacokinetic and pharmacodynamic variability in renal transplant recipients (RTR) attributed to P-glycoprotein (P-gp), an ABCB1 efflux transporter that influences bioavailability and intracellular distribution. Data on race and sex influences on P-gp in RTR are lacking. We investigated sex and race influences on cyclosporine pharmacokinetics and ABCB1 gene expression in peripheral blood mononuclear cells (PBMC). Fifty-four female and male African American and Caucasian stable RTR receiving cyclosporine and mycophenolic acid completed a 12-hour study. ABCB1 gene expression was assessed in PBMCs pre-dose and 4 hours after cyclosporine. Statistical analysis used mixed effects models on transformed, normalized ABCB1 expression and cyclosporine pharmacokinetics. Sex and race differences were observed for the dose-normalized area under the concentration curve (AUC0-12 /Dose) [P = .0004], apparent clearance [P = .0004] and clearance/body mass index (CL/BMI) [P = .027] with slowest clearance and greatest drug exposure in females. Sex and race differences were found pre-dose and 4 hours for ABCB1 [P < .0001] with females having less expression than males. ABCB1 differences were observed between pre-dose and 4 hours [P = .0009]. Female RTR had slower cyclosporine clearance and lower ABCB1 gene expression in PBMC suggesting reduced efflux activity and greater intracellular drug exposure.

Reduction of free fatty acids, safety, and pharmacokinetics of oral GS-9667, an A(1) adenosine receptor partial agonist.

GS-9667, a new selective, partial agonist of the A(1) adenosine receptor (AR), may represent an effective therapy for Type 2 diabetes (T2DM) and dyslipidemia via lowering of free fatty acids (FFA). The objectives of the studies were to evaluate the effects of single and multiple doses of GS-9667 on plasma FFA concentrations, its pharmacokinetics (PK) and safety/tolerability. Two studies were conducted. In the single ascending dose study, healthy, non-obese, and obese subjects received a single oral dose of GS-9667 (30-1,800 mg). In the multiple, ascending dose study, healthy, obese subjects received GS-9667 (600-2,400 mg QD, 1,200 mg BID, or 600 mg QID) for 14 days. Blood and urine samples were collected for lipid profiling and PK analyses. The ECG, vital signs, and subject tolerability were monitored. Doses of GS-9667 ≥300 mg caused dose-dependent reductions in FFA levels that were reproducible over 14 days without evidence of desensitization or rebound. All doses were well tolerated. GS-9667 was rapidly absorbed and distributed; Steady-state concentrations were achieved within 3-5 days. The A(1) AR partial agonist GS-9667 reduced plasma FFA, exhibited linear kinetics, and was well-tolerated in healthy non-obese and obese subjects.

Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension.

The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects.

Dose range evaluation of Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, in combination with amphotericin B-desoxycholate for treatment of murine systemic candidiasis.

Systemic candidiasis causes significant mortality in patients despite amphotericin B (AMB) therapy. Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, is closely related to Mycograb, which showed a survival advantage in combination with AMB in a phase III human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. In our study, the interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by using a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans infections were used to assess the in vivo interaction between 1.4 mg/kg of body weight/day of DAMB and 0.15, 1.5, and 15 mg/kg/day of the Mycograb C28Y variant after 1, 3, and 5 days of therapy. DAMB and Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multidose pharmacokinetics for the Mycograb C28Y variant were determined. Indifference or synergy between DAMB and the Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the Mycograb C28Y variant was best described by a 2-compartment model with a median serum t(1/2)(α) of ~0.198 h and a t(1/2)(ß) of ~1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (P > 0.05 by analysis of variance). The Mycograb C28Y variant alone had no antifungal activity. We therefore conclude that the Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis.

Mycophenolic acid pharmacokinetics during maintenance immunosuppression in African American and Caucasian renal transplant recipients.

Renal transplant recipients exhibit variability in mycophenolic acid (MPA) and MPA glucuronide (MPAG) pharmacokinetics, which are influenced by clinical and demographic factors. Racial influence on MPA and MPAG pharmacokinetics was investigated in 53 patients: 17 African American males, 22 Caucasian males, and 14 females receiving mycophenolate mofetil (MMF) and cyclosporine. A 12-hour steady-state pharmacokinetic study was conducted. Enterohepatic circulation of MPA was characterized by a second plasma concentration peak and was included in a novel statistical model with MPAG. MPA clearance in African American males was 26.5 ± 14.4 L/h versus 17.9 ± 6.1 L/h in Caucasian males (P = .035) and 16.1 ± 4.6 L/h in Caucasian females (P = .024) with no difference noted in MPA troughs. Enterohepatic circulation occurred less frequently in African American males (23%) compared with Caucasian males (42%) and Caucasian females (50%) (P > .05). Cyclosporine exposure was correlated with MPA and MPAG pharmacokinetics, whereas creatinine clearance influenced MPAG pharmacokinetics. A racial difference was noted with more rapid MPA clearance in African American males compared with Caucasians. The results support differential MPA dosing and the role of therapeutic drug monitoring in addition to considering the influence of renal function and concurrent immunosuppressives on MPA and MPAG pharmacokinetics.