Applying interpretable machine learning workflow to evaluate exposure-response relationships for large-molecule oncology drugs.

The application of logistic regression (LR) and Cox Proportional Hazard (CoxPH) models are well-established for evaluating exposure-response (E-R) relationship in large molecule oncology drugs. However, applying machine learning (ML) models on evaluating E-R relationships has not been widely explored. We developed a workflow to train regularized LR/CoxPH and tree-based XGboost (XGB) models, and derive the odds ratios for best overall response and hazard ratios for overall survival, across exposure quantiles to evaluate the E-R relationship using clinical trial datasets.

Complete mitochondrial genome of from wuhu, China (Rotifera, Brachionidae).

The complete mitochondrial genome of was sequenced using primers design, clone culture, DNA extraction, LONG-PCR amplification, purification and clone sequencing. We found that it is composed of two circular chromosomes, designated mtDNA I (11,398 bp) and mtDNA II (12,820 bp). The gene content of the mitochondrial genome was similar to that of the previously reported mitochondrial genome of .

Application of a Two-Analyte Integrated Population Pharmacokinetic Model to Evaluate the Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Polatuzumab Vedotin in Patients with Non-Hodgkin Lymphoma.

Purpose: The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing.

Methods: Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions.

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Purpose: The CD79b-targeted antibody-drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure.

Methods: The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI-142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]).

Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma.

Exposure-response relationships were investigated to assess the risk/benefit of polatuzumab vedotin (pola) + bendamustine-rituximab (pola + BR) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Analyses were conducted in pivotal study GO29365 (NCT02257567; BR/pola + BR/pola + BG [BG: bendamustine-obinutuzumab]; 1.8 mg/kg pola, every 3 weeks [Q3W], six cycles), and supportive studies DCS4968g (NCT01290549) and GO27834 (NCT01691898) (pola/pola + R/pola + G; 0.

Physiologically-Based Pharmacokinetic Model-Informed Drug Development for Fenebrutinib: Understanding Complex Drug-Drug Interactions.

Fenebrutinib is a CYP3A substrate and time-dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically-based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug-drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B.

Integrated Two-Analyte Population Pharmacokinetic Model of Polatuzumab Vedotin in Patients With Non-Hodgkin Lymphoma.

A two-analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non-Hodgkin lymphoma. A two-compartment model with a nonspecific, time-dependent linear clearance, a linear time-dependent exponentially declining clearance, and a Michaelis-Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two-compartment model.

Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer.

Purpose: The phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug-drug interactions (DDIs) were assessed.

Methods: Pharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed.

Exposure-Response-Based Product Profile-Driven Clinical Utility Index for Ipatasertib Dose Selection in Prostate Cancer.

The aims of this work were to characterize ipatasertib exposure-response (E-R) relationships in a phase II study and to quantitatively assess benefit-risk using a clinical utility index approach to support ipatasertib phase III dose selection in patients with metastatic castration-resistant prostate cancer. Logistic regression and Cox proportional-hazards models characterized E-R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose interruptions/reductions (modifications) were tested in the E-R models.

Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens.

Aims: We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer.

Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R ).

A Phase I Pharmacokinetic Study of Trastuzumab Emtansine (T-DM1) in Patients with Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer and Normal or Reduced Hepatic Function.

Objective: The aim of this study was to evaluate the pharmacokinetics (PK) of trastuzumab emtansine (T-DM1) and relevant analytes in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and hepatic impairment.

Methods: Patients were enrolled in three independent parallel cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment, and moderate hepatic impairment. Patients received T-DM1 3.

Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug-Drug Interaction Prediction.

Background And Objectives: Physiologically based pharmacokinetic (PBPK) modeling for itraconazole has been challenging due to highly variable in vitro d ata used for 'bottom-up' model building. Under-prediction of pharmacokinetics and drug-drug interactions (DDIs) following multiple doses of itraconazole has limited the use of PBPK model simulation to aid an itraconazole clinical DDI study design. The aim of this work is to develop an itraconazole PBPK model predominantly using a 'top-down' approach to enable a more accurate pharmacokinetic and DDI prediction.

Crystal structure of (4-fluoro-phenyl-κC (1))iodido-(N,N,N',N'-tetra-methyl-ethylenedi-amine-κ(2) N,N')palladium(II).

In the title compound, [Pd(C6H4F)I(C6H16N2)], the Pd(II) atom is coordinated by two N atoms from the N,N,N',N'-tetra-methyl-ethylenedi-amine ligand, a C atom of the 4-fluoro-phenyl group and an iodide ligand in a distorted square-planar geometry, with an average deviation from the least-squares plane through the ligand donor atoms of 0.0159 (2) Å. The angles about the Pd(II) atom range from 83.

Semi-mechanistic Multiple-Analyte Pharmacokinetic Model for an Antibody-Drug-Conjugate in Cynomolgus Monkeys.

Purpose: A semi-mechanistic multiple-analyte population pharmacokinetics (PK) model was developed to describe the complex relationship between the different analytes of monomethyl auristatin E (MMAE) containing antibody-drug conjugates (ADCs) and to provide insight regarding the major pathways of conjugate elimination and unconjugated MMAE release in vivo.

Methods: For an anti-CD79b-MMAE ADC the PK of total antibody (Tab), conjugate (evaluated as antibody conjugated MMAE or acMMAE), and unconjugated MMAE were quantified in cynomolgus monkeys for single (0.3, 1, or 3 mg/kg), and multiple doses (3 or 5 mg/kg, every-three-weeks for 4 doses).

Physiologically based pharmacokinetic modeling as a tool to predict drug interactions for antibody-drug conjugates.

Background And Objectives: Monomethyl auristatin E (MMAE, a cytotoxic agent), upon releasing from valine-citrulline-MMAE (vc-MMAE) antibody-drug conjugates (ADCs), is expected to behave like small molecules. Therefore, evaluating the drug-drug interaction (DDI) potential associated with MMAE is important in the clinical development of ADCs. The objective of this work was to build a physiologically based pharmacokinetic (PBPK) model to assess MMAE-drug interactions for vc-MMAE ADCs.

Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates.

Purpose: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates.

Methods: Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies.

The complete mitochondrial genome of the Acrossocheilus fasciatus (Cyprinidae, Barbinae).

The mitochondrial genome of Acrossocheilus fasciatus (Cyprinidae, Barbinae) is a circular molecule of 16,589 bp in length, containing 37 typical animal mitochondrial genes: 13 protein-coding genes (PCGs), 2 r RNAs, 22 t RNAs and a non-coding D-loop region. Its gene order and arrangement are identical to the common type found in most fish mitogenomes. All PCGs start with a typical ATG codon except for COI which use GTG as a start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the ND2, ND3, ND4, COII, Cytb and COIII which use single T or TA as a stop codon.

The complete mitochondrial genome of the Zacco platypus, Huangshan, China (Cypriniformes: Cyprinidae, subfamily Daninninae).

The mitochondrial genome of Zacco platypus (Cypriniformes: Cyprinidae, subfamily Daninninae) is a circular molecule of 16,611 bp in length, containing 37 typical animal mitochondrial genes: 13 protein-coding genes (PCGs), 2 ribosomal RNAs, 22 transfer RNAs and a D-loop region. Its gene order and arrangement are identical to the common type found in most fish mitogenomes. All PCGs start with a typical ATG codon except for COI which use GTG as start codon; all PCGs terminate in the common stop codon TAA or TAG, except for the COII which use single T as stop codon.

Daily dosing of vismodegib to steady state does not prolong the QTc interval in healthy volunteers.

Introduction: Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval.

Methods And Results: Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed.

Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding.

Purpose: In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics.

Experimental Design: Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points.

[Expression of EBI3 and p28 mRNA in the brain and spinal cord of chronic model of experimental autoimmune encephalomyelitis in C57BL/6J mice].

Objective: To investigate the expression of EBI3 and p28 mRNA (the 2 subunits of IL-27) in the brain and spinal cord of the model of experimental autoimmune encephalomyelitis (EAE), and to explore their effect on EAE.

Methods: Seventy-two adult female SPF C57BL/6J mice (inbred strain) were randomly divided into a control group, an adjuvant group, and an EAE group. RT-PCR was performed to detect the expression of EBI3 mRNA and p28 mRNA in the brain and spinal cord.

[Mouse model of experimental antoimmune encephalomyelitisin C57BL/6J and expression of macrophage migration inhibitory factor].

Objective: To detect the expression of macrophage migration inhibitory factor(MIF) in the brain and spinal cord of chronic non-remitting model of experimental autoimmune encephalomyelitis(EAE) mouse, and to discuss their effect on EAE/MS.

Methods: Seventy-two female SPF C57BL/6J mice, aged 6k8 weeks, were randomly divided into an EAE group, a blank group, and an adjuvant group. The mice were immuned by mMOG35-55 and CFA.

[A preparative method of chronic experiment autoimmune encephalomyelitis].

Objective: To explore the model of chronic experimental autoimmune encephalomyelitis (EAE)for the further study of multiple sclerosis.

Methods: A total of 72 female SPF C57BL/6J mice (inbred strain, aged 8 approximately 10 weeks), were randomly divided into an EAE group, a blank group and an adjuvant group, and each group was divided into 3 subgroups: an onset group, a peak group and a chronic phase group. The EAE group was immunized with mMOG35-55.