Clinical Pharmacology Profile Research Articles

Model-Informed Clinical Pharmacology Profile of a Novel Fixed-Dose Combination of Nivolumab and Relatlimab in Adult and Adolescent Patients with Solid Tumors.

Progression-free survival (PFS) was significantly improved with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination (FDC) every 4 weeks (Q4W) versus nivolumab alone in patients with previously untreated advanced melanoma in RELATIVITY-047. In addition, RELATIVITY-020 (Part D) demonstrated a manageable safety profile and potential for durable response with nivolumab plus relatlimab in previously treated patients. Here, we evaluate the clinical pharmacology profile (CPP) of nivolumab plus relatlimab to support the approved regimen for adult and adolescent patients with advanced melanoma and its continued clinical development in solid tumors. The pharmacokinetics (PK) and immunogenicity of relatlimab and nivolumab were assessed using data from RELATIVITY-047 and RELATIVITY-020. Patients with advanced solid tumors received relatlimab alone or nivolumab plus relatlimab as single-agent vials (SAV) or FDC. PK was characterized using a population PK (popPK) model. Relatlimab demonstrated nonlinear and time-varying PK. Nonlinearity in relatlimab PK represented approximately 31% of total CL of relatlimab 160 mg Q4W. Relatlimab PK was dose proportional at doses ≥160 mg Q4W. Geometric mean exposures were similar for SAV and FDC cohorts receiving equivalent dosing regimens. No dose adjustment was required for covariates. Incidence of relatlimab antidrug antibodies was <6% for nivolumab plus relatlimab and had no clinically meaningful impact. There was no PK-related drug interaction of nivolumab plus relatlimab. The CPP of relatlimab alone or in combination with nivolumab supports the approved dosing in advanced melanoma and the continued evaluation of nivolumab and relatlimab across other solid tumors. See related commentary by Gopalakrishnan and Amaria, p. 2862.

Clinical Pharmacology Profile of AMG119, the First Chimeric Antigen ReceptorT (CAR-T) Cell Therapy Targeting Delta-Like Ligand3 (DLL3), in Patients with Relapsed/Refractory Small Cell Lung Cancer (SCLC).

With the promise of a potentially single-dose curative regimen, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with 6 approved products in the USA. However, there are no approved CAR-T cell therapies for solid tumors. Herein, we report the clinical pharmacology profile of AMG119, the first CAR-T cell therapy targeting delta-like ligand3 (DLL3), in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC). AMG119 demonstrated robust cellular expansion with long-lasting cell persistence and a favorable exposure-response relationship. AMG119 has been demonstrated to be clinically safe and well tolerated at the doses tested, with no dose-limiting toxicities (DLTs) reported. This is the first publication of the clinical pharmacology profile of a CAR-T cell therapy in SCLC, with encouraging cellular kinetics data supporting the potential for CAR-T cell therapy in solid tumor space.

Ixekizumab for the treatment of moderate-to-severe plaque psoriasis: the first septennium.

Ixekizumab is a humanized monoclonal antibody that specifically inhibits IL-17A. It has been approved for the treatment of adult and pediatric psoriasis, psoriatic arthritis and axial spondyloarthropathies by the US FDA and the EMA. Phase III trials, post hoc analyses and real-life data have reported its efficacy, effectiveness and safety. This review summarizes the latest evidence on the clinical efficacy, pharmacology and safety profile of ixekizumab for the treatment of moderate-to-severe psoriasis. A literature search was performed for articles published through December 2022. Ixekizumab is one of the most efficacious biologics for psoriasis, with a rapid onset of response, favorable long-term outcomes and an adequate safety profile.

A Phase 1 First-in-human Study to Investigate the Safety, Tolerability and Food Effect of ABBV-CLS-7262 (P6-4.002)

<h3>Objective:</h3> To evaluate the first-in-human safety, tolerability and food effect of ABBV-CLS-7262 in healthy subjects. <h3>Background:</h3> ABBV-CLS-7262 is in development as a CNS-penetrant small molecule activator of eIF2B, which is the guanine nucleotide exchange factor for eukaryotic translation initiation factor 2 (eIF2). eIF2 is an important node in the Integrated Stress Response, which is believed to be persistently activated in various neurological diseases, including amyotrophic lateral sclerosis. By activating eIF2B, ABBV-CLS-7262 may attenuate the Integrated Stress Response and restore protein translation. <h3>Design/Methods:</h3> This multi-part Phase 1 study enrolled healthy male and female subjects between 18 and 65 years of age. A total of 125 subjects received ABBV-CLS-7262 and 33 received placebo. <h3>Results:</h3> ABBV-CLS-7262 was well-tolerated following oral administration of single and multiple ascending doses for up to 14 days. All adverse events (AEs) were mild to moderate in severity, and no dose-dependent patterns of AEs or laboratory abnormalities were identified. Following administration with a high-fat meal, the safety, tolerability, and pharmacokinetics were similar when compared to the fasting state. <h3>Conclusions:</h3> The observed safety, tolerability, and clinical pharmacology profile of ABBV-CLS-7262 support investigation of the product in further studies. <b>Disclosure:</b> Dr. Cho has received personal compensation for serving as an employee of Calico. Dr. Cho has stock in Roche. Dr. Jeong has received personal compensation for serving as an employee of AbbVie. An immediate family member of Dr. Jeong has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Stryker. Dr. Jeong has stock in AbbVie. Dr. Malik has received personal compensation for serving as an employee of AbbVie. Dr. Malik has received personal compensation for serving as an employee of Calico Life Sciences. Dr. Boiser has received personal compensation for serving as an employee of AbbVie. Dr. Boiser has stock in AbbVie. Dr. Huang has received personal compensation for serving as an employee of AbbVie. Dr. Rosebraugh has received personal compensation for serving as an employee of AbbVie Inc. Dr. Rosebraugh has stock in AbbVie Inc..

Phase I/II study to assess the clinical pharmacology and safety of single ascending and multiple subcutaneous doses of PF-06881894 in women with non-distantly metastatic breast cancer

PurposeTo evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of single and multiple doses of PF-06881894 (pegfilgrastim-apgf; Nyvepria™), a biosimilar to reference pegfilgrastim (Neulasta®), in women with non-distantly metastatic breast cancer.MethodsIn Phase I (Cycle 0) of this Phase I/II study, the PD response (absolute neutrophil count [ANC]; CD34 + count), PK profile, and safety of a single 3- or 6-mg subcutaneous dose of PF-06881894 were assessed in chemotherapy-naïve patients before definitive breast surgery. In Phase II (Cycles 1–4), the PD response (duration of severe neutropenia [DSN, Cycle 1], ANC [Cycles 1 and 4]) and PK profile (Cycles 1 and 4) of single and multiple 6-mg doses of PF-06881894 concomitant with chemotherapy and after definitive breast surgery were assessed.ResultsTwenty-five patients (mean age 59 years) were enrolled (Cycle 0, n = 12; Cycles 1–4, n = 13). In Cycle 0, PD responses and PK values were lower with 3-mg versus 6-mg PF-06881894. In Cycles 1 and 4, mean DSN was 0.667 days after single or multiple 6-mg doses of PF-06881894, respectively. In Cycle 4 versus Cycle 1, PD responses were more robust; PK values (mean area under the curve, maximum concentration) were lower; and clearance values were higher. The safety profile of PF-06881894 was similar to that for reference pegfilgrastim.ConclusionPF-06881894 as a single 3- or 6-mg dose prior to definitive surgery, or multiple 6-mg/cycle doses postoperatively, with/without myelosuppressive chemotherapy, was consistent with the clinical pharmacology and safety profile of reference pegfilgrastim.Trial registrationOctober 2017. ClinicalTrials.gov Identifier: NCT02650193. EudraCT Number: 2015-002057-35.

Drug-Disease Interaction and Time-Dependent Population Pharmacokinetics of Isatuximab in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a monoclonal antibody (mAb) of immunoglobulin G (IgG) isotype, specifically targets the cluster of differentiation 38 antigen overexpressed in malignant plasma cells. Isatuximab is used to treat multiple myeloma (MM), characterized by the excessive production of abnormal “myeloma proteins” (M‐proteins) that may interact with therapeutic IgG mAb on the neonatal Fc receptor (FcRn)‐mediated recycling pathway. The clinical pharmacology profile of isatuximab was investigated by population pharmacokinetics (PKs) modeling in 476 patients with MM who received 1–20 mg/kg isatuximab either as single agent or in combination with pomalidomide‐dexamethasone in 4 clinical trials. Isatuximab PKs were characterized by a two‐compartment model with parallel time‐varying linear clearance (CL) and nonlinear elimination. Due to a mechanism‐based drug‐disease interaction, patients secreting IgG M‐protein exhibited a twofold lower drug exposure compared with patients with non‐IgG MM. No dose adjustment was required based on MM immunoglobulin type because efficacy and safety profiles were comparable between IgG and non‐IgG MM subpopulations. β2‐microglobulin, body weight, sex, drug material, and race have a limited effect on drug exposure and do not require any dose adjustment. A typical 50% decrease in linear CL from initial treatment to steady‐state was predicted, and this decrease correlated with the best overall response rate and was slower for patients with IgG MM. These findings suggest that the time‐dependent effect of isatuximab is likely mediated by a combined factor of both disease state evolution and the perturbation of the FcRn‐mediated recycling pathway.

Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists.

Coronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological properties. Prasugrel and ticagrelor are more potent and have a faster onset of action; however, they have shown an increased bleeding risk compared with clopidogrel. Cangrelor is highly potent and has a very rapid onset and offset of effect; however, its indication is limited to P2Y12 antagonist-naïve patients undergoing percutaneous coronary intervention. Two novel P2Y12 receptor antagonists are currently in clinical development, namely vicagrel and selatogrel. Vicagrel is an analog of clopidogrel with enhanced and more efficient formation of its active metabolite. Selatogrel is characterized by a rapid onset of action following subcutaneous administration and developed for early treatment of a suspected acute myocardial infarction. This review article describes the clinical pharmacology profile of marketed P2Y12 receptor antagonists and those under development focusing on pharmacokinetic, pharmacodynamic, and drug-drug interaction liability.

Sarecycline Review.

Objective: Sarecycline is a new oral tetracycline antibiotic recently approved by the US Food and Drug Administration. The aim of this article was to evaluate the data from published clinical trials of sarecycline in the treatment of acne, review the drug's pharmacology, and understand how this new medication may apply to clinical practice. Data Sources: A systematic literature review was performed using the terms sarecycline (Seysara), P005672, and WC-3035 in the MEDLINE and EMBASE databases. ClinicalTrials.gov was searched to identify ongoing or nonpublished studies. Study Selection and Data Extraction: Articles in English between January 2000 and April 2019 relating to clinical trials, pharmacology, safety, and microbiological profile were evaluated. Data Synthesis: In a phase 3 clinical trial (SC1401), absolute change from baseline in facial inflammatory lesion count at week 12 was -15.3 for the sarecycline arm and -10.1 for placebo (P < 0.01). In another phase 3 clinical trial (SC1402), the absolute change in this category was -15.7 for sarecycline and -10.7 for placebo (P < 0.01). Mean percentage change in facial inflammatory lesion count was higher in the sarecycline group than in the placebo group in both studies (P < 0.01). Relevance to Patient Care and Clinical Practice: The 1.5-mg/kg sarecycline dose has efficacy in reducing inflammatory lesions, is well tolerated, and has more targeted antimicrobial activity, which may help reduce the risk of developing antibiotic resistance. Conclusions: This novel, once-daily treatment may represent a useful treatment for patients with moderate to severe acne.

Population pharmacokinetic meta-analysis of ramucirumab in cancer patients.

AimsRamucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor‐2 (VEGFR‐2) and blocks binding of VEGF‐A, VEGF‐C and VEGF‐D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach.MethodsA total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an intravenous infusion over 1 h at 8 mg kg−1 every 2 weeks or 10 mg kg−1 every 3 weeks. A series of pharmacostatistical models were developed to describe the concentration data. The best model was used to evaluate patient factors for their effect on ramucirumab pharmacokinetics.ResultsThe pharmacokinetics of ramucirumab were well characterized by a two‐compartment model. Mean population estimates of clearance, volume of distribution and half‐life for a typical 68‐kg patient were 0.0148 l h−1, 5.30 l and 13.4 days, respectively. A modest relationship was observed between body weight and ramucirumab disposition; clearance and central compartment volume increased with body weight. No other patient characteristics were shown to influence the disposition of ramucirumab in this patient population.ConclusionsThe final model adequately described the concentration–time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight‐normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment.

Clinical pharmacology profile of care in Hepatology clinic.

Since 2010, the Clinical Gastroenterology and Hepatology Division of the Central Institute of Hospital das Clínicas of the University of São Paulo Medical School (HC-FMUSP, in the Portuguese acronym) has been developing specialized electives assistance activities in the Outpatient Specialty Clinic, Secondary Level, in São Paulo NGA-63 Várzea do Carmo. The objective of this study was to analyze the pharmacotherapeutic profile of patients. This is a cross-sectional and retrospective study in which patients were seen at the Hepatology sector and the results were submitted to descriptive statistics. During the study period, 492 patients were treated at the clinic, with a mean age of 58.9 years and frequency of 61.2% female and 74.8% living in São Paulo. This population was served by various other medical specialties (cardiology and endocrine among others) and the major liver diagnoses were: chronic hepatitis B and C and fatty liver. Comorbidities were also identified, such as diabetes, hypertension and dyslipidemia. Most patients took their medication in the Basic Health Units. We found that 30% of patients use of more than five medications and the most prescribed were omeprazole 208 (42.3%), metformin 132 (26.8%) and losartan 80 (16.3%). Because it is an adult/elderly population, with several comorbidities and polymedication, it is important to be aware of the rational use of medication. The multidisciplinary team is important in applying correct conducts for the safe use of medicines, to reduce the burden on health spending and improving the quality of life of patients.

Model-Based Population Pharmacokinetic Analysis of Nivolumab in Patients With Solid Tumors.

Nivolumab is a fully human monoclonal antibody that inhibits programmed death‐1 activation. The clinical pharmacology profile of nivolumab was analyzed by a population pharmacokinetics model that assessed covariate effects on nivolumab concentrations in 1,895 patients who received 0.3–10.0 mg/kg nivolumab in 11 clinical trials. Nivolumab pharmacokinetics is linear with a time‐varying clearance. A full covariate model was developed to assess covariate effects on pharmacokinetic parameters. Nivolumab clearance and volume of distribution increase with body weight. The final model included the effects of baseline performance status (PS), baseline body weight, and baseline estimated glomerular filtration rate (eGFR), sex, and race on clearance, and effects of baseline body weight and sex on volume of distribution in the central compartment. Sex, PS, baseline eGFR, age, race, baseline lactate dehydrogenase, mild hepatic impairment, tumor type, tumor burden, and programmed death ligand‐1 expression had a significant but not clinically relevant (<20%) effect on nivolumab clearance.

Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrate-resistant prostate cancer clinical studies

Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrate-resistant prostate cancer clinical studies

Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C

Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, ledipasvir reaches maximum plasma concentrations (T max) 4-4.5h post-dose and is eliminated with a terminal half-life (t 1/2) of 47h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma (T max: 0.8-1h; t 1/2: 0.5h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4h post-dose; the elimination t 1/2 for GS-331007 is 27h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for ledipasvir/sofosbuvir.

Clinical Implications of Riociguat Pharmacokinetics and Pharmacodynamics: Introduction to the Riociguat Clinical Pharmacology Supplement

Riociguat (BAY 63-2521) is a novel oral soluble guanylate cyclase (sGC) stimulator developed for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).1 It targets the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) pathway and, via a dual mode of action, both stimulates sGC directly, independently of NO, and sensitizes sGC to endogenous NO by stabilizing NO-sGC binding. As a result, riociguat restores the NO-sGC-cGMP pathway, increasing intracellular levels of cGMP,1-3 thereby addressing the imbalance of vasoconstriction over vasodilation that is present in the lung vasculature of patients with pulmonary hypertension (PH).4 Riociguat has been evaluated in a rigorous clinical trial program, including two large randomized, double-blind, placebo-controlled phase 3 studies, PATENT-1 and CHEST-1, and their respective long-term extension studies, PATENT-2 and CHEST-2. These studies have shown that riociguat can improve exercise capacity, hemodynamic function, and quality-of-life parameters in patients with PAH or CTEPH.5-8 Data from the clinical trial program have also shown riociguat to be well tolerated and to have a favorable safety profile that was sustained over long-term treatment. Most of the observed side effects are consistent with the vasodilatory effects of the drug, such as headache, dizziness, and hypotension, and adverse events were evenly matched between riociguat and placebo treatment groups. Syncope was an adverse event of special interest, but in the two pivotal trials the incidences of serious syncope events were higher in the placebo groups than in the riociguat groups. Few patients discontinued treatment as a result of adverse events.5-10 On the basis of these studies, riociguat was the first therapy to be approved for the treatment of two indications: PAH, as demonstrated in patients with etiologies of idiopathic or heritable PAH or PAH associated with connective-tissue disease, and inoperable or persistent/recurrent CTEPH.9,10 Patients with congenital heart disease were also included in the PATENT studies.11 Riociguat is now licensed in more than 50 countries worldwide, including European countries, the United States, Canada, and Japan. Additional clinical trials are ongoing to investigate the efficacy and tolerability of riociguat in other indications, including PH associated with idiopathic interstitial pneumonia (ClinicalTrials.gov identifier: NCT02138825). In addition to the phase 3 studies, riociguat has a comprehensive clinical pharmacology portfolio based on a series of pharmacokinetic (PK) and pharmacodynamic (PD) studies. The choice of clinical pharmacology studies conducted with riociguat was guided by the PK (e.g., drug-drug interactions based on known metabolism) and PD (e.g., known hemodynamic/vasoactive activity) properties of riociguat, in addition to the typical characteristics of the PH patient population (e.g., patient covariates, such as renal/hepatic function, and potential concomitant medication use, such as warfarin). PK profiling of riociguat was of particular interest because of the observed direct link between riociguat exposure and its hemodynamic activity, as demonstrated in initial clinical pharmacology and proof-of-concept studies12,13 and later supported by a population PK and PD analysis from the phase 3 studies.14 Evidence from these studies facilitates the safe and effective use of riociguat, as reflected in the US prescribing information10 and the European summary of product characteristics,9 and helps to inform physicians making treatment decisions. This supplement includes a collection of the PK and PD studies conducted with riociguat, to provide a complete clinical pharmacology profile of the drug in both healthy volunteers and patients with PAH and CTEPH.

Clinical Pharmacology Profile of Pacritinib (PAC), a Novel JAK2/FLT3 Inhibitor

Introduction: PAC is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R that does not inhibit JAK1. PAC has demonstrated activity in phase (Ph) 1-3 clinical studies. Nonclinical and clinical pharmacokinetic (PK) and pharmacodynamic studies support a 400 mg QD oral dosing regimen in ongoing Ph 3 studies in myelofibrosis. Here we present PK data from a series of Ph 1 studies of PAC.Methods: Seven Ph 1 studies were conducted in healthy subjects receiving a single 100, 200, or 400 mg dose of PAC. In an ADME mass balance study, [14 C]-PAC was administered to characterize routes of disposition. Separate drug interaction studies were conducted to assess effects of a strong CYP3A4 inhibitor (clarithromycin) or strong pan-CYP450 inducer (rifampin) on PAC PK. Cardiac safety of PAC was evaluated in a thorough QT (TQT) study. Food-effect, dose proportionality, and relative bioavailability studies were also conducted.Results: 140 subjects across 7 studies received single doses of PAC 100-400 mg. PK parameters of PAC 400 mg are presented in the Table (n=12). Following administration of single 100-400 mg PAC doses under fasted conditions, systemic exposure increased in a linear, but less than dose proportional manner. Among identified metabolites, the 2 major metabolites (M1, M2) exhibit relatively low pharmacological potency and are unlikely to contribute to PAC activity. Following a 400 mg single dose of [14 C]-PAC, the parent compound was the predominant moiety in plasma. Mean radioactivity recovery in urine = 3.22% of administered dose with intact PAC excreted in urine = 0.12% of administered dose. Of all 9 metabolites formed, M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose) excreted in urine. Mean radioactivity recovery in feces = 85.46% of administered dose and M2 (O- dealkylation metabolite) was the predominant component (24.08% of administered dose). When co-administered with clarithromycin (CYP3A4 inhibitor), PAC exposure increased with mean Cmax and AUC approximately 1.3- and 1.8-fold higher, respectively, with a similar mean t1/2 vs PAC alone. Co-administration with rifampin, a strong CYP3A4 inducer, reduced mean PAC Cmax and AUC by 51% and 87%, respectively vs PAC alone. Median Tmax was similar when co-administered with rifampin vs PAC alone (5-6 h), but t1/2 was shortened by approximately 65% (PAC: 43.3 h; PAC + rifampin: 15.1 h). Administration of single oral doses of PAC 400 mg in a placebo- and moxifloxacin-controlled TQT study had no clinically relevant effects on ECG parameters, including heart rate. There was no effect on QT prolongation (mean QTcF change <10 msec) and a small but non-clinically significant shortening in the placebo-corrected change in QTcF below 0 msec in the first 12 h post-dose. Across all clinical pharmacology studies, PAC was tolerable (primarily grade 1 gastrointestinal AEs), consistent with the PAC clinical safety profile to date.Conclusions: PAC exhibits moderate oral bioavailability and is eliminated primarily through metabolism and biliary excretion. Minimal excretion occurs via renal clearance, indicating dosage adjustment is unlikely to be warranted in renal impairment. Increase in PAC exposure is limited when co-administered with a strong CYP3A4 inhibitor, unlikely necessitating dosage adjustments. There is marked reduction in systemic exposure when co-administered with a strong CYP450 inducer and co-administration should therefore be avoided due to potential for negative impact on efficacy. PAC was not found to cause QT prolongation, suggesting favorable cardiac safety. Single 100-400 mg doses of PAC were well tolerated in healthy volunteers in these studies. Overall, PAC exhibited a favorable clinical pharmacology profile supportive of its safety and tolerability at clinical dose levels.TablePK Parameter(Geometric Mean; n=12)PAC 400 mgCmax, μg/mL3.83AUC0-t, μg∙h/mL184t1/2, h37.5Tmaxa, h6.00λz, L/h0.0185CL/F, L/h2.08Vz/F, L112Oral bioavailability, %58.6aMedian for Tmax.λz, terminal elimination rate constant; AUC0-t, area under the plasma concentration curve from time 0 to time t; CL/F, apparent oral clearance; Cmax, maximum plasma concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Vz/F apparent volume of distribution during terminal phase. DisclosuresAl-Fayoumi:CTI Biopharma: Employment, Equity Ownership. Off Label Use: This abstract discusses off-label use of pacritinib. Campbell:CTI Biopharma: Equity Ownership. Amberg:BMS: Employment, Equity Ownership; Juno: Equity Ownership. Zhou:CTI Biopharma: Employment, Equity Ownership. Millard:CTI Biopharma Corp.: Employment. Dean:CTI Biopharma: Employment, Equity Ownership.

Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: focus on drug-drug interactions.

Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies.

The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist.

The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105h, whereas the calculated effective half-life is 48h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25h. Clearance values are not significantly different in adolescents (~13.0ml/min) and the elderly (~10.5ml/min) compared with adults (10.9ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12mg, but not 4 or 8mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.

Development of apixaban: a novel anticoagulant for prevention of stroke in patients with atrial fibrillation.

The factor Xa inhibitor apixaban is one of the novel anticoagulants to emerge as alternatives to long-standing standards of care that include low-molecular-weight heparin and warfarin. The development of apixaban reflects a strategy to optimize the clinical pharmacology profile, dosing posology, trial designs, and statistical analyses across multiple indications, and to seek alignment with global health authorities. The primary objective of dose selection was to maintain balance between efficacy and bleeding risk. Twice-daily dosing of apixaban, rather than once daily, was chosen to lower peak concentrations and reduce fluctuations between peak and trough levels. Our discussion here focuses on the use of apixaban for stroke prevention in nonvalvular atrial fibrillation (NVAF). Supporting this indication, a pair of registrational trials was conducted that enrolled the full spectrum of patients who, by guidelines, were eligible for anticoagulation. In the AVERROES study of patients who were unsuitable for warfarin therapy, apixaban was superior to aspirin in reducing the risk of stroke or systemic embolism (SSE), without a significant increase in major bleeding (MB). In the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation) study, apixaban was superior to warfarin on the rates of SSE, MB, and all-cause mortality. Overall, these studies have demonstrated a substantially favorable benefit–risk profile for apixaban over warfarin and aspirin in NVAF.

Model‐based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma

AimIpilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4. The objective of the present study was to characterize the clinical pharmacology profile of ipilimumab using a population pharmacokinetic (PPK) approach.MethodsThe PPK model was developed using 2095 ipilimumab serum concentration values from 499 patients with unresectable stage III or IV melanoma from four phase II studies, with ipilimumab doses ranging from 0.3 to 10 mg kg−1. The structural PK model was determined by developing a base PPK model. The effect of covariates on model parameters was assessed by a full covariate model, which incorporated all pre-specified covariate-parameter relationships into the base model. The final model was developed by backward elimination, followed by exclusion of covariates determined not to be of clinical relevance to ipilimumab, and was rigorously validated against both internal and external datasets.ResultsIpilimumab PK was linear and time-invariant, with dose-proportional exposures over the available dose range, yielding a terminal half-life of approximately 15 days. Clearance of ipilimumab increased with increasing body weight and baseline serum lactate dehydrogenase concentrations, but was not affected by age, gender, concomitant budesonide, Eastern Cooperative Oncology Group performance status or prior systemic anticancer therapy. Furthermore, ipilimumab exposure was not affected by moderate renal impairment or mild hepatic impairment.ConclusionsIpilimumab concentration–time data were well described by a linear, two compartment, zero order i.v. infusion model. The model confirms that a body weight-normalized dosing regimen is appropriate for ipilimumab therapy in patients with advanced melanoma.

Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor

Vorinostat is a histone deacetylase inhibitor that has demonstrated preclinical activity in numerous cancer models. Clinical activity has been demonstrated in patients with a variety of malignancies. Vorinostat is presently indicated for the treatment of patients with advanced cutaneous T cell lymphoma (CTCL). Clinical investigation is ongoing for therapy of other solid tumors and hematological malignancies either as monotherapy or in combination with other chemotherapeutic agents. This review summarizes the pharmacokinetic properties of vorinostat. Monotherapy pharmacokinetic data across a number of pharmacokinetic studies were reviewed, and data are presented. In addition, literature review was performed to obtain published Phase I and II pharmacokinetic combination therapy data to identify and characterize potential drug interactions with vorinostat. Pharmacokinetic data in special populations were also reviewed. The clinical pharmacology profile of vorinostat is favorable, exhibiting dose-proportional pharmacokinetics and modest food effect. There appear to be no major differences in the pharmacokinetics of vorinostat in special populations, including varying demographics and hepatic dysfunction. Combination therapy pharmacokinetic data indicate that vorinostat has a low propensity for drug interactions. Vorinostat's favorable clinical pharmacology and drug interaction profile aid in the ease of administration of vorinostat for the treatment of advanced CTCL and will be beneficial in continued assessment for other oncologic indications. Although a number of studies have been conducted to elucidate the detailed pharmacokinetic profile of vorinostat, more rigorous assessment of vorinostat pharmacokinetics, including clinical drug interaction studies, will be informative.