Prediction of relative change in free nerve growth factor following subcutaneous administration of tanezumab, a novel monoclonal antibody to nerve growth factor.

Tanezumab is a monoclonal antibody against nerve growth factor (NGF). We investigated tanezumab pharmacokinetic (PK)-NGF relationships and predicted the extent of systemic free NGF suppression with target-mediated drug disposition (TMDD) modeling using data from three pivotal phase III interventional studies (NCT02697773, NCT02709486, and NCT02528188) in patients with osteoarthritis. Patients received tanezumab 2.5 mg or 5 mg every 8 weeks (q8w) subcutaneously. A TMDD model using a previously established population PK model was used to describe plasma tanezumab and serum total NGF concentration data, and simulations were performed to predict "unobserved" free NGF versus time profiles and dose-response relationships for free NGF. A total of 2992 patients had available data for plasma tanezumab or serum total NGF concentrations and were included in the analysis; 706 of these had data for both tanezumab and total NGF concentrations. The model generally performed well to predict observed total NGF concentrations up to ~24 weeks after each dose. Simulations suggested free NGF concentration would be suppressed by ~75% (median) near the peak of tanezumab concentration and by less than 5% (median) around the trough tanezumab concentration with a tanezumab 2.5 mg q8w regimen. Free NGF concentration was predicted to return to baseline level at ~8 weeks (95% prediction interval: 5-16 weeks) after the last tanezumab dose. This model adequately described plasma tanezumab and serum total NGF concentrations following s.c. administration of tanezumab 2.5 or 5 mg q8w, allowed prediction of relative change in systemic free NGF following s.c. administration of tanezumab.

Population pharmacokinetics of tanezumab following intravenous or subcutaneous administration to patients with osteoarthritis or chronic low back pain.

AIMS: Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. METHODS: Data from 10 studies of IV or SC tanezumab (2.5-20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2-compartment model with linear and nonlinear elimination (based on prior analysis of pre-2015 IV osteoarthritis studies) was expanded to include other pre-2015 studies. In Step 2, post-2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment-emergent anti-drug antibodies (TE ADA). RESULTS: SC bioavailability was estimated at 62-76%. The key disposition parameters CL, Vc , Vp and KM were estimated to be 0.133 L d-1 , 2.6 L, 1.77 L and 31.2 µg L-1 , respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9-11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5-10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4-8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6-7%). CONCLUSION: Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK.

Pharmacokinetics and exploratory efficacy biomarkers of bococizumab, an anti-PCSK9 monoclonal antibody, in hypercholesterolemic Japanese subjects
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OBJECTIVE: Bococizumab, a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, has been shown to reduce low-density lipoprotein cholesterol (LDL-C). Here, we describe the pharmacokinetics and pharmacodynamics of bococizumab and its effect on lipoprotein particle composition and other biomarkers, based on a double-blind, placebo-controlled, randomized, dose-ranging study. MATERIALS AND METHODS: The study consisted of two populations: Japanese subjects with uncontrolled LDL-C (LDL-C ≥ 100 mg/dL) despite treatment with atorvastatin (n = 121) and Japanese subjects naïve to lipid-lowering agents with LDL-C ≥ 130 mg/dL (n = 97). Subjects were randomized to receive either bococizumab 50, 100, or 150 mg or placebo, every 2 weeks. One arm of subjects in the ator-vastatin-treated population received ezetimibe 10 mg instead of bococizumab. RESULTS: In both populations, bococizumab exposure increased with increasing dose, and subjects with lower body weights tended to have higher exposures. Bococizumab treatment was associated with a dose-dependent reduction in LDL particles and a small increase in total high-density lipoprotein (HDL) particles. Significant reductions in lipoprotein-associated phospholipase A2 (Lp-PLA2) were observed for bococizumab-treated subjects but not for subjects treated with placebo or ezetimibe. CONCLUSION: Increased bococizumab dosage resulted in increased exposure. Levels of LDL and HDL particles and biomarkers such as Lp-PLA2 were also altered with bococizumab treatment. (ClinicalTrials.gov identifier: NCT02055976).
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Does Industry-Conducted All-Case Surveillance of Newly Approved Oncology Drugs Contribute to the Revision of Package Inserts in Japan?

In Japan, the Pharmaceuticals and Medical Devices Agency requires all-case surveillance studies (ACSS) for many novel oncology drugs as a condition for approval. However, this is a major burden on the pharmaceutical industry and clinicians. The objective of this analysis was to investigate whether ACSS can contribute essential new information on severe adverse drug reactions, which are necessary to revise the package inserts of drugs. All oncology drugs for which ACSS were required from January 2006-September 2015 found on the Pharmaceuticals and Medical Devices Agency website were reviewed, and the influence of ACSS on the package insert content was evaluated. Most of the package insert revisions regarding serious treatment-related adverse events were based on spontaneous reports from clinicians. The contribution of ACSS results to the revision of package inserts is limited and comes at the cost of financial resources and labor. An alternative, more efficient adverse-event reporting system is necessary.

Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults.

PURPOSE: These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties. METHODS: An open-label, randomized, crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal. Point estimates and 90% CIs for geometric mean ratios were generated for Cmax, AUC0-∞, and AUC0-t. FINDINGS: Cmax and AUC met bioequivalence criteria for crushed tablets in water. Cmax and AUC decreased by 21.1% and 16.4%, respectively, with the lower bound of the CIs falling below the bioequivalence criteria for crushed tablets with applesauce. Similarly, administration of whole tablets with a high-fat, high-calorie meal reduced apixaban Cmax and AUC by 14.9% and 20.1%, respectively. The exposure reductions in both studies were considered not clinically significant. IMPLICATIONS: Apixaban tablets can be administered crushed or whole, with or without food. The results of these alternative methods of administration support their use in patients who have difficulty swallowing tablets. ClinicalTrials.gov identifiers: NCT02101112 and NCT01437839.

A phase I study of the human anti-activin receptor-like kinase 1 antibody PF-03446962 in Asian patients with advanced solid tumors.

Preclinical studies suggest that ALK-1 signaling mediates a complementary angiogenesis pathway activated upon development of resistance to vascular endothelial growth factor (VEGF)-targeted therapies. Inhibition of ALK-1 signaling may lead to disruption of tumor angiogenesis and growth. We report findings from a multicenter, open-label, phase I study of the fully human anti-ALK-1 mAb PF-03446962 conducted in Japan and South Korea, in Asian patients with advanced solid tumors. The dose escalation Part 1 of the study was based on a standard 3 + 3 design (n = 16). In Part 2, patients were treated with PF-03446962 at 7 and 10 mg/kg (10/cohort), including patients with disease progression following prior VEGF receptor (R)-targeted therapy. Primary objectives were determination of the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity of PF-03446962. No dose-limiting toxicity (DLT) was noted in the 12 DLT-evaluable patients. Treatment was well tolerated. The MTD for biweekly intravenous administration was estimated to be 10 mg/kg and the RP2D 7 mg/kg. Treatment-related grades 1-3 thrombocytopenia was experienced by 27.8% patients. The most frequent nonhematologic treatment-related AEs were grades 1-2 pyrexia and epistaxis. Four patients (3/4 with hepatocellular carcinoma) developed telangiectasia suggesting vascular targeting and in vivo ALK-1 inhibition by PF-03446962. Stable disease for 12 weeks or more was observed in 25.7% of patients and in 44.4% of those with hepatocellular carcinoma. ALK-1 inhibition by PF-03446962 may represent a novel antiangiogenic strategy for patients with advanced solid malignancies complementary to current treatment with VEGF(R)-targeted inhibitors or chemotherapy.

[Quantitative Decision Making in Drug Development: Pharmacometrics].

According to the US Food and Drug Administration, pharmacometrics is an emerging science that quantifies drugs, diseases, and trial information to aid efficient drug development and/or regulatory decisions. Quantitative decision making occurs at all stages of drug development. In general, patient-level data are not made available to competitors. However, summary-level data are available. Model-based meta-analysis (MBMA) is a powerful tool for decision making which identifies the candidate position in the market. The limitation of MBMA is the heterogeneity of the treatment effect. In the near future, MBMA application is expected at every stage of drug development.

Axitinib plasma pharmacokinetics and ethnic differences.

Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted.

Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions.

Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.

Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability - considerations for drug development.

INTRODUCTION: Drug transporter proteins are expressed on the cell membrane, regulating substrate exposure in systemic circulation and/or peripheral tissues. Genetic polymorphism of drug transporter genes encoding these proteins could alter the functional activity and/or protein expression, having effects on absorption, distribution, metabolism and excretion (ADME), efficacy and adverse effects. AREAS COVERED: The authors provide the reader with an overview of the pharmacogenetics (PGx) of 12 membrane transporters. The clinical literature is summarized as to the quantitative significance on pharmacokinetics (PK) and implications on pharmacodynamics (PD) and adverse effects, due to transporter influence on intracellular drug concentrations. EXPERT OPINION: Unlike polymorphisms for cytochrome P450s (CYPs) resulting in large magnitude of PK variation, genetic mutations for membrane transporters are typically less than threefold alteration in systemic PK for drugs with a few exceptions. However, substantially greater changes in intracellular drug levels may result. We are aware of 1880 exome variants in 12 of the best-studied transporters to date, and nearly 40% of these change the amino acid. However, the functional consequences of most of these variants remain to be determined, and have only been empirically evaluated for a handful. To the extent that genetic polymorphisms impact ADME, it is a variable that will contribute to ethnic differences due to substantial frequency differences for the known variants.

Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients.

BACKGROUND: Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3. We report on data obtained from 18 Japanese patients with advanced solid tumors in two phase I trials that evaluated the safety, pharmacokinetics and antitumor activity of axitinib and also examined potential biomarkers. METHODS: Six patients received a single 5-mg dose of axitinib followed by 5 mg twice daily (BID), and an additional six patients received axitinib 5 mg BID only. Another six patients received axitinib at 5-mg, 7-mg and 10-mg single doses followed by 5 mg BID. RESULTS: Plasma pharmacokinetics following single doses of axitinib was generally linear. Common treatment-related adverse events were fatigue (83%), anorexia (72%), diarrhea (67%), hand-foot syndrome (67%) and hypertension (61%). Sixteen patients (89%) experienced thyroid-stimulating hormone (TSH) elevation. Grade 3/4 toxicities included hypertension (33%) and fatigue (28%). No grade 3/4 fatigue occurred in patients who started thyroid hormone replacement therapy when TSH was elevated. Thyroglobulin elevation was observed in all patients who continued treatment with axitinib for ≥3 months. Abnormal TSH correlated with exposure to axitinib (r = 0.72). Decrease in soluble (s) VEGFR-2 levels significantly correlated with exposure to axitinib (r = -0.94). Axitinib showed antitumor activity across multiple tumor types. CONCLUSIONS: Axitinib-related thyroid dysfunction could be due to a direct effect on the thyroid gland. Grade 3/4 fatigue and hypothyroidism appear to be controllable with use of thyroid hormone replacement therapy. sVEGFR-2 and TSH may act as biomarkers of axitinib plasma exposure.

A new strategy toward the total synthesis of stachyflin, a potent anti-influenza A virus agent: concise route to the tetracyclic core structure.

[reaction: see text] A new strategy directed toward the total synthesis of stachyflin, a potent and novel anti-influenza A virus agent isolated from a microorganism, has been presented through the enantioselective synthesis of the tetracyclic core structure. The synthetic method features a BF(3) x Et(2)O-induced domino epoxide-opening/rearrangement/cyclization reaction as the key step.