Exposure-efficacy Relationships Research Articles

Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients.

Venetoclax is a first in class BCL-2 inhibitor, currently under investigation for the treatment of t(11;14) multiple myeloma (MM). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax when combined with carfilzomib and dexamethasone (VenKd) in t(11;14)-positive relapsed or refractory (R/R) MM patients from a phase 2 study. Fifty-seven patients receiving VenKd or Kd were included in the analysis. Efficacy endpoints included progression-free survival and clinical response rates of overall response, very good partial response or better and complete response or better. Grade ≥ 3 neutropenia, Grade ≥ 3 infections, Grade ≥ 3 treatment-emergent adverse events and any grade serious treatment-emergent adverse events were evaluated. The analysis demonstrated that adding venetoclax to Kd resulted in increased ORR, ≥VGPR and ≥ CR rates compared to the control arm. Within the venetoclax treatment arms (VenKd), no significant exposure-efficacy relationships were observed for ORR and ≥ VGPR rates. Higher ≥ CR rates trended with higher venetoclax exposures. While both 400mg and 800mg venetoclax in VenKd arms were generally tolerated, higher rates of Grade ≥ 3 neutropenia were observed with higher venetoclax exposures. Higher venetoclax exposures however were not associated with increased rates of Grade ≥ 3 treatment-emergent adverse events, Grade ≥ 3 infections, or serious treatment-emergent adverse events (any grade). These results confirm the benefit of adding venetoclax to carfilzomib and dexamethasone and support continued evaluation of venetoclax 400-800mg once daily in this combination in t(11;14)-positive R/R MM patients. NCT02899052 registered April 18, 2017.

Population Pharmacokinetic Modeling and Exposure-Efficacy and Body Weight-Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.

Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen.

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit-risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high-grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use. These tolerability concerns may be contributed by or compounded by inadequate dose optimization. The recommended dosing regimen of copanlisib 60 mg administered on days 1, 8, and 15 of a 28-day cycle was selected as the maximal tolerated dose (MTD) during phase I. Thus, this analysis sought to justify the copanlisib dose regimen selection. Copanlisib exposure-efficacy relationships were considered from its large phase III trial, CHRONOS-3, whereas copanlisib safety was investigated by pooling data across its two large clinical trials to comprehensively assess its exposure-safety relationships. Results demonstrated a statistically significant positive linear exposure-efficacy relationship at the MTD. Exposure-safety analyses revealed a borderline significant linear relationship for grade ≥3 TEAEs and no significant exposure-safety relationships for other investigated safety end points. The model-based benefit/risk framework considered the established exposure-response models and defined clinical utility function which confirmed the appropriateness of the copanlisib dosing regimen across the range of its achieved exposures.

A Bayesian optimal interval design for dose optimization with a randomization scheme based on pharmacokinetics outcomes in oncology.

The primary objective of an oncology dose-finding trial for novel therapies, such as molecularly targeted agents and immune-oncology therapies, is to identify the optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. Pharmacokinetic (PK) information is considered an appropriate indicator for evaluating the level of drug intervention in humans from a pharmacological perspective. Several novel anticancer agents have been shown to have significant exposure-efficacy relationships, and some PK information has been considered an important predictor of efficacy. This paper proposes a Bayesian optimal interval design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients allocated to OD in various realistic settings.

A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991. Intravenous infusion using vascular access button (VAB) technology was found to best reproduce clinical target exposures of AZD5991 in mice. Exposure-efficacy relationships were evaluated, demonstrating that dissimilar PK profiles result in differences in target engagement and efficacy outcomes. Thus, these data underscore the importance of accurately ascribing key PK metrics in the translational process to enable clinically meaningful predictions of efficacy.

Bioanalytical Assays for Pharmacokinetic and Biodistribution Study of Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are produced by the chemical linkage of cytotoxic agents and monoclonal antibodies. The complexity and heterogeneity of ADCs and the low concentration of cytotoxic agent released in vivo poses big challenges to their bioanalysis. Understanding the pharmacokinetic behavior, exposure-safety, and exposure-efficacy relationships of ADCs is needed for their successful development. Accurate analytical methods are required to evaluate intact ADCs, total antibody, released small molecule cytotoxins, and related metabolites. The selection of appropriate bioanalysis methods for comprehensive analysis of ADCs is mainly dependent on the properties of cytotoxic agents, the chemical linker, and the attachment sites. The quality of the information about the whole pharmacokinetic profile of ADCs has been improved due to the development and improvement of analytical strategies for detection of ADCs, such as ligand-binding assays and mass spectrometry-related techniques. In this article, we will focus on the bioanalytical assays that have been used in the pharmacokinetic study of ADCs and discuss their advantages, current limitations, and potential challenges. SIGNIFICANCE STATEMENT: This article describes bioanalysis methods which have been used in pharmacokinetic study of ADCs and discusses the advantages, disadvantages and potential challenges of these assays. This review is useful and helpful and will provide insights and reference for bioanalysis and development of ADCs.

The pulmonary biopharmaceutics and anti-inflammatory effects after intratracheal and intravenous administration of Re-Du-Ning injection

BackgroundRe-Du-Ning injection (RDN) is a renowned heat-clearing traditional Chinese medicine for the treatment of respiratory diseases owing to its anti-inflammatory effects. However, very little is known about the pulmonary distribution and lung exposure–efficacy relationships. This study aimed to investigate the pulmonary distribution and biopharmaceutics concerning lung penetrability and affinity and the local anti-inflammatory effects after intravenous and pulmonary administration of RDN. MethodsTwo iridoids and seven phenolic acid components were selected as the chemical markers in RDN. The in vitro pulmonary distribution and biopharmaceutics were conducted by evaluating the binding and disassociation kinetics of chemical markers in lung tissue explants whereas the in vivo evaluation was performed by determining the time-dependent concentrations of chemical markers in plasma, lung epithelial lining fluid (ELF), lung tissues and immune cells in the ELF after intratracheal and intravenous administrations of RDN. The inhibitory effects on tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production were used to evaluate the anti-inflammatory effect of RDN on lung tissues in vitro and on mice with LPS-induced lung inflammation. ResultsThe chemical markers of RDN exhibited excellent lung penetrability but poor lung affinity in vitro and in vivo. After intravenous administration, the chemical markers appeared to rapidly penetrate through the lung tissue to reach the ELF, leading to markedly higher drug exposure to ELF and immune cells in the ELF than to lung tissues. Compared to intravenous injection, the intratracheal instillation of RDN increased drug exposure to lung tissue and immune cells in the ELF by up to > 80-fold, leading to improved anti-inflammatory potency and prolonged duration of action. ConclusionThe drug exposure to immune cells in the ELF was correlated with the lung-targeted anti-inflammatory effects of RDN and pulmonary delivery has the potential to replace intravenous injection of RDN for the treatment of respiratory diseases.

Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology.

Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. Poly (ADP-ribose) polymerase inhibitors are potent inhibitors of the PARP enzymes with comparable half-maximal inhibitory concentrations in the nanomolar range. Olaparib and rucaparib are orally dosed twice a day, extensively metabolized by cytochrome P450 enzymes, and inhibitors of several enzymes and drug transporters with a high risk for drug-drug interactions. Niraparib and talazoparib are orally dosed once a day with a lower risk for niraparib and a minimal risk for talazoparib to cause drug-drug interactions. All four PARP inhibitors show moderate-to-high interindividual variability in plasma exposure. Higher exposure is associated with an increase in toxicity, mostly hematological toxicity. For talazoparib, exposure-efficacy relationships have been described, but for olaparib, niraparib, and rucaparib this relationship remains inconclusive. Further studies are required to investigate exposure-response relationships to improve dosing of PARP inhibitors, in which therapeutic drug monitoring could play an important role. In this review, we give an overview of the pharmacokinetic properties of the four PARP inhibitors, including considerations for patients with renal dysfunction or hepatic impairment, the effect of food, and drug-drug interactions. Furthermore, we focus on the pharmacodynamics and summarize the available exposure-efficacy and exposure-toxicity relationships.

P-042: POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSIS OF HYDROXYUREA, IN ADULT PATIENTS WITH SICKLE CELL DISEASE (SCD) RECEIVING BOTH TABLETS OR CAPSULES FORMULATIONS, AND EVALUATION OF DISEASE MARKERS

Purpose: Hydroxycarbamide (HU) is used sickle-cell disease (SCD) after having showed to induce fetal haemoglobin (HbF)[1]. Although this was an old molecule, few pharmacokinetics-pharmacodynamics (PK/PD) models were developed on HU. 1.Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008; 358 (13): 1362-69. 10.1056/NEJMct0708272. Materials and methods: The aim of this analysis was to develop retrospectively, a population PK (popPK) and PK/PD models to patients receiving both HU formulations (capsules or tablets), in order to: Describe the exposure-efficacy relationships between HU and biomarkers (HbF% and mean corpuscular volume (MCV)) Compare PK/PD parameters, HbF% and MCV, obtained with the results observed in Paule et al[1], Simulate HbF% and MCV levels according to two regimens (7/7 vs 5/7 days) for 14 weeks at 1000 mg daily dose. We combine three PK datasets from renal study[1], bioequivalence study[2] and retrospective PKPD data from patients followed in hospital Mondor. A popPK model for HU was established. The selected popPK model was used in PK/PD modelling, consisting of two independent PK/PD models respectively for HbF% and MCV. Indirect PK/PD models were tested for both relations since drug impact on each marker was observed after few weeks of treatment. 1.Clinical study report, “Evaluation of the impact of renal function on the pharmacokinetics of hydroxyurea (siklos®) in normal-renal, hyperfiltrating and renal failure sickle cell disease patients (DARH)”. Final version, 02-February-2018. 2.Clinical study report, “a phase I pharmacokinetics study of hydroxyurea 1,000 mg coated breakable tablets and hydroxyurea 500 mg capsules in paediatric, adolescent and adult patient treated for sickle cell syndrome”. Final version, 15 april 2005. 1.Paule I, Sassi H, Habibi A, Pham KP, Bachir D, Galactéros F, Girard P, Hulin A, Tod M. Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen. Orphanet Journal of Rare Diseases. 2011. Results: The popPK model was confirmed as a linear model with a 2-compartment parameterized in terms of CL/F, V2/F, Q/F, V3/F and ka, allometric scale with exponents of 0.75 and 1 for clearances and volumes of distribution, respectively was integrated. For a bodyweight of 70 kg, clearance was 12.1 L/h with a variability of 63.9%, V2/F and V3/F were respectively 48.1 and 31.1 L. Population parameters were very closed to observed CL/F and V/F obtained in the study published by Paule et al2. Conclusion: Precision of the model was acceptable and individual prediction of HbF% levels were good (Figure 1). For MCV, HU is assumed to reduce kout (inhibition of the elimination of the response) (Figure 2). Regarding simulations, MCV reached a plateau around 3 months of HU and HbF% continue to increase over 14 weeks (Figure 3). Indeed, the increase of HbF% and MCV levels was more marked than using the regimen with 2 days of HU interruption (especially in patients having the highest values). The daily regimen seemed to be more appropriate regarding both responses. Both HbF% and MCV are good biomarkers for evaluation of SCD.Figure 1. pcVPC of level of HbF% vs. time after treatment initiation (left: lin-lin scale; right: lin-log scale) Figure 2. pcVPC of level of MCV vs. time after treatment initiation (left: lin-lin scale; right: lin-log scale)Figure 3. SIMULATED HBF% AND MCV LEVELS USING PKPD MODEL, CONSIDERING 2 DOSING REGIMENS (left: HBF%; right: MCV) The authors do not declare any conflict of interest

Exposure–response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations

PurposeTepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.MethodsExposure–efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure–safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30–1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia’s method (QTcF).ResultsTepotinib exhibited flat exposure–efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure–safety relationships for all endpoints within the exposure range observed with 30–1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.ConclusionsThese analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.Registration NumbersNCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

Abstract 5422: Exploring the feasibility of longer dosing intervals in a population with relapsed/refractory classic Hodgkin's lymphoma based on population pharmacokinetics modeling analysis

Abstract Background: Penpulimab is a humanized IgG1 monoclonal antibody that blocks PD-1 binding to PD-L1. During the dose-escalation phase, no dose-limiting toxicity event was observed, and the maximum administered dose(MAD) was 10 mg/kg Q2W. The RO% of all dose groups (1.0, 3.0 and 10.0 mg/kg Q2W) reached 80%~100%. Penpulimab was administered in a fixed dosing regimen (200 mg Q2W) in a phase II study (AK105-201) demonstrating efficacy and safety in R/R cHL patients. Longer dosing intervals may offer greater flexibility and convenience to both patients and healthcare professionals. So we explored the feasibility of a longer dosing regimen (200 mg Q3W and 400 mg Q6W). Methods: A penpulimab population PK (PPK) model was established based on PK data from a total of 332 subjects from six clinical studies. The following PK parameters were determined and used in subsequent analyses: Cmin,ss, Cmax,ss, AUCss. Exposure-response (ER) evaluation was conducted using univariate logistic regression. The efficacy endpoints included complete response (CR), overall response rate (ORR) and disease control rate (DCR) in AK105-201 study. Safety endpoints included grade ≥ 3 treatment-related adverse event (TRAE), grade ≥ 3 immune-related adverse events (irAE), or AE leading to suspension in all the six clinical studies. PK simulation was conducted using the PPK model among different regimens (200 mg Q3W and 400 mg Q6W vs. 200 mg Q2w regimen), and in comparison with Cmin,ss of 3 μg/mL (6 x concentration for 80% RO in vitro). Result: The final PPK structural model for penpulimab was a two-compartment model with first-order elimination. Body weight correlated with volume of distribution but the effect is not considered clinically significant, supporting fixed dose in subsequent studies. Relatively flat ER relationships were observed betwedn the efficacy endpoints (CR, ORR and DCR) and PK exposure (simulated Cmax,ss, Cmin,ss, AUCss) in R/R cHL patients. No apparent correlation was observed between PK exposure and safety response in patients with different types of cancer. The PK simulation showed that the steady-state concentration-time curves for 200 mg Q2W or 3 mg/kg Q2W administration were generally consistent. Compared to the 200 mg Q2W regimen, the mean Cmin,ss of 200 mg Q3W and 400 mg Q6W regimens were approximately 36.5% and 55.5% lower, respectively. But in both cases, the Cmin,ss of 97.5% of the population were higher than 3 μg/mL, suggesting sufficient receptor occupancy. The Cmax,ss and AUCss under the 400 mg Q6W regimen were lower than MAD(10 mg/kg Q2W). Conclusions: The conducted analyses support fixed dosing and showed relatively flat exposure-efficacy and exposure-safety relationships. PK simulations suggest that both 200 mg Q3W or 400 mg Q6w could offer similar efficacy and safety as compared to 200 mg Q2W, while allow greater flexibility and convenience. Citation Format: Benchao Chen, Yongcheng Dong, Jin Xiao, Max Wang, Dennis Xia, Michelle Xia, Baiyong Li. Exploring the feasibility of longer dosing intervals in a population with relapsed/refractory classic Hodgkin's lymphoma based on population pharmacokinetics modeling analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5422.

Therapeutic Drug Monitoring of the Echinocandin Antifungal Agents: Is There a Role in Clinical Practice? A Position Statement of the Anti-Infective Drugs Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still used. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies. A literature search was conducted using PubMed in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics (PKs), pharmacodynamics (PDs), drug-drug interactions, TDM, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on PD/PD (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized. Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported. Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed.

P612 Mirikizumab Pharmacokinetics and Exposure - Efficacy Relationships in Patients with Ulcerative Colitis

Abstract Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy in a Phase 2 trial in patients with moderately-to-severely active ulcerative colitis (UC)1 (NCT02589665). Analyses of the pharmacokinetics (PK) of miri and the relationships between exposure and efficacy at Week 12 are reported. Methods Patients were randomised to receive IV placebo, miri 50 mg or 200 mg with possibility of exposure-based dose increases, or miri 600 mg every 4 weeks, with efficacy assessment at Week 12. Serum concentrations of miri were analyzed using population PK methods. Population models were also used to evaluate the relationships between various clinical efficacy measures at Week 12 and miri exposure. The effects of patient factors on both PK and exposure-efficacy relationships were evaluated. Model-based and graphical methods were also used to understand the potential for confounded relationships between miri exposure and efficacy. Results A systemic clearance of 0.023 L/hr was estimated for miri, similar to estimates in healthy subjects and patients with psoriasis. Miri exposure increased in a linear manner. Patients with lower serum albumin concentration or lower body weight tended to have significantly higher clearance or lower volume of distribution, respectively (p<0.01); however, the magnitude of the impact was small and contributed less than 15% to random variability. The model-based exposure-response analyses generally showed that patient factors had a stronger impact on efficacy at Week 12 than miri exposure. Prior biologic experience and baseline rectal bleeding (RB) score had significant impacts (p<0.01) on the estimated placebo effect and maximal miri treatment effect (Emax), respectively. In the clinical response model, the estimated placebo response rate was 20 percentage points higher in biologic naïve vs experienced patients. The estimated response rate at a miri dose of 600mg was 28% higher in patients with a baseline RB≥2. Inclusion of these factors in the exposure-efficacy models caused the estimated EC50 to drop substantially, suggesting that the post-hoc exposure-efficacy relationships are likely confounded based on these patient factors. Graphical evaluations also suggested the presence of confounding factors. Conclusion Miri PK in UC patients was consistent with PK observed in healthy subjects and psoriasis patients. Evaluation of the relationships between miri exposure and efficacy in UC patients accounted for the potential impact of patient factors. Confounding patient factors may distort the true cause-effect relationship between exposure and efficacy and were carefully considered in support of optimal selection of doses for miri Phase 3 studies. Reference 1. Gastroenterology. 2020;158(3):537–549.

Pharmacokinetics and exposure-efficacy relationships of omalizumab in patients with nasal polyps

The anti-immunoglobulin E (IgE) antibody, omalizumab (Xolair), is approved in the United States for the treatment of allergic asthma and chronic spontaneous urticaria, and has recently been studied for the treatment of nasal polyposis following completion of the two replicate phase 3 studies (POLYP 1 and POLYP 2). The dosing of omalizumab used in the phase 3 studies is based on a combination of patients’ pre-treatment IgE level and body weight, similar to the approach used in allergic asthma. The objectives of the current analyses were to evaluate whether the pharmacokinetics (PK) of omalizumab and its pharmacodynamic (PD) effect on free and total IgE level in chronic rhinosinusitis with nasal polyps (CRSwNP) are consistent with those in allergic asthma via population PK/PD modeling and simulation, and to graphically explore exposure-response relationships and free IgE-response relationships in CRSwNP. Omalizumab PK and PD effect of total and free IgE in CRSwNP are generally consistent with those in asthma. Observed post-treatment free IgE suppressions were generally within the target range of the baseline IgE- and body weight-based omalizumab dosing table, with 74.2% and 93.0% of patients achieving a serum free IgE level below 25 ng/mL and 50 ng/mL, respectively at Week 24. Exposure-response analyses indicated that there was no clear correlation between omalizumab or free IgE concentration and key efficacy endpoints within the POLYP studies. Overall, these results indicate that the body weight and IgE-based dosing regimen of omalizumab was appropriate for use in CRSwNP patients.

P.307 Effect of zuranolone on depression and anxiety outcomes in postpartum depression in a randomized, placebo-controlled trial

To characterize, in adolescents aged 12–17, the pharmacokinetic (PK) profile of perampanel, the impact of intrinsic and extrinsic factors on PK, and the relationships between perampanel exposure and cognitive function, seizure frequency, and responder status.Population PK analysis used plasma concentration data from Phase II study 235 (NCT01161524), in which adolescents with inadequately controlled POS despite treatment with 1–3 antiepileptic drugs (AEDs) were randomized to receive once daily oral placebo or perampanel (8–12 mg/day) for 19 weeks, pooled with data from adolescent patients in perampanel Phase III studies 304, 305, 306. Exposure–cognition and exposure–efficacy relationships were modelled using data from study 235.Population PK results from 152 adolescent patients revealed a perampanel apparent clearance of 0.729 L/h, consistent with previous analyses in adolescents and adults. Clearance was increased with coadministration of inducing AEDs (carbamazepine, oxcarbazepine and phenytoin), and was slightly higher in females. The PK/pharmacodynamics (PD) analysis for cognition (n = 110) showed that increasing perampanel exposure had no significant effect on overall cognition, measured by the Cognitive Drug Research global cognition score. The PK/PD analysis for efficacy (n = 123) showed a significant decrease in seizure frequency and significant increased probability of being a responder, as perampanel concentration increased − both in the presence and absence of inducing AEDs. Carbamazepine, oxcarbazepine and phenytoin reduced perampanel exposure in adolescents, but reduced the magnitude of seizure frequency reduction and responder probability to a lesser extent.Significance: Pharmacokinetics of perampanel are similar in adolescents to adults. Increasing perampanel exposure reduces seizure frequency and increases probability of being a responder regardless of concomitant inducers. The lack of relationship between perampanel exposure and cognitive function suggests a benign cognitive profile for this AED in adolescents. We await results from long-term exposure.

Clinical Pharmacokinetics and Pharmacodynamics of the Cyclin-Dependent Kinase 4 and 6 Inhibitors Palbociclib, Ribociclib, and Abemaciclib.

Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food-effect and drug-drug interaction studies, and highlight exposure-response and exposure-toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40-95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure-efficacy relationship has been described, while for palbociclib and ribociclib exposure-response analyses remain inconclusive. Future studies are needed to address exposure-efficacy relationships to further improve dosing.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism

Anticoagulant plasma concentrations and patient characteristics might affect the benefit–risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN–DVT and EINSTEIN–PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure–response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure–efficacy relationships were shallow. Exposure–safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit–risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

A clinical decision support tool may help to optimise vedolizumab therapy in Crohn’s disease

SummaryBackgroundA clinical decision support tool (CDST) has been validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn’s disease.AimTo assess the utility of this CDST for predicting exposure‐efficacy and disease outcomes.MethodsUsing data from three independent datasets (GEMINI, GETAID and VICTORY), we assessed clinical remission rates and measured VDZ exposure, rapidity of onset of action, response to dose optimisation and progression to surgery by CDST‐defined response groups (low, intermediate and high).ResultsA linear relationship existed between CDST‐defined groups, measured VDZ exposure, rapidity of onset of action and efficacy in GEMINI through week 52 (P < 0.001 at all time points across three CDST‐defined groups). In GETAID, CDST predicted differences in clinical remission at week 14 (AUC = 0.68) and rapidity of onset of action (P = 0.04) between probability groups. The high‐probability patients did not benefit from shortening of infusion intervals, and differences in onset of action between the high‐intermediate and low‐probability groups within GETAID were no longer significant when including low‐probability patients who received a week 10 infusion. CDST predicted a twofold increase in surgery risk over 12 months of VDZ therapy among low‐ to intermediate‐probability vs high‐probability patients (adjusted HR 2.06, 95% CI 1.33‐3.21).ConclusionsWe further extended the clinical utility of a previously validated VDZ CDST, which accurately predicts at baseline exposure‐efficacy relationships and rapidity of onset of action and could be used to help identify patients who would most benefit from interval shortening and those most likely to require surgery while on active therapy.

Exposure-Response Relationship of the Bruton Tyrosine Kinase Inhibitor, Zanubrutinib (BGB-3111) in Patients with Hematologic Malignancies

Background: Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible inhibitor of Bruton tyrosine kinase (BTK), currently in phase 3 development for the treatment of hematologic malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM). In a dose escalation study evaluating doses of 40, 80, 160, and 320 mg once daily and 160 mg twice daily, no dose limiting toxicities were observed and maximum tolerated dose (MTD) was not established. Objective responses have been observed in patients with various B-cell malignancies (including CLL, MCL, WM) at all tested dose levels. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (Tam et al. Blood 2016;128:642). To support dose selection, this exposure-response (E-R) analysis evaluated exposure-safety and exposure-efficacy (in MCL) relationships in patients with B-cell malignancies receiving zanubrutinib monotherapy. Methods: A population pharmacokinetic (PopPK) model was developed from 600 subjects enrolled in 9 clinical studies in patients with B-cell malignancies and healthy volunteers. Exposure data such as steady-state area under the plasma concentration time curve (AUC0-24,ss), maximum observed plasma concentration (Cmax ) or steady state trough concentration (Cmin) derived from the PopPK analysis were used in the E-R analysis. Exposure-efficacy analyses were performed using exposure metrics and overall response rate (ORR) data from two studies in patients with relapsed/refractory (R/R) MCL (n=51), including Study 206, a pivotal Phase 2 study conducted in China and study AU-003, a global Phase 1, dose escalation/cohort expansion study. The efficacy endpoint evaluated was ORR, as assessed by an independent review committee (IRC) as well as by investigators, according to 2014 Lugano Classification. Exposure-safety analyses were conducted using data from 4 studies in patients with B-cell malignancies (n=372) receiving zanubrutinib as monotherapy at a total daily dose from 40 mg to 320 mg. The safety endpoints evaluated included Grade ≥ 3 adverse events (AE) and AEs of interests, including neutropenia, thrombocytopenia, anemia, infections/infestations, all events of secondary primary malignancies, all events of atrial fibrillation and flutter, major bleeding events, and any bleeding events. Results: PopPK analysis demonstrated that race, body weight, age, CrCL, sex, tumor type, and use of acid-reducing agents did not show a statistically significant impact on the PK of zanubrutinib. The PK profile of zanubrutinib was comparable between Asians and non-Asians, which allows for bridging of clinical efficacy and safety data across the pivotal studies conducted globally (AU-003) and in China (206). The analysis showed that the median AUC0-24,ss and Cmax values were 1736 ng·h/mL and 275 ng/mL in responders compared with 1326 ng·h/mL and 175 ng/mL in nonresponders, respectively. Although overall median exposure (AUC0-24,ss, Cmax) was higher in responders compared with nonresponders, no significant E-R relationship was identified for efficacy based on probability of observing ORR and logistic regression model (Fig 1). The E-R relationships based on investigator assessments were consistent with those based on IRC assessments. For the exposure-safety analysis, the exposure ranges were similar in patients experiencing adverse events of interests relative to those who were not. There were no evident E-R relationships between PK exposure (AUC0-24,ss, Cmax, or Cmin) and the probability to have adverse events of interest (eg., Fig. 2). Conclusion: E-R analyses indicate that higher plasma exposures of zanubrutinib were not associated with higher probability to have adverse events across the dose range of 40 mg to 320 mg in patients with B-cell malignancies. This result supports the recommended dose of 160 mg twice daily in patients with MCL, based on high rates of objective response in patients with R/R MCL, generally favorable safety and tolerability profiles, and complete and sustained BTK occupancy in PBMCs and target tissues at this dose. Disclosures Ou: BeiGene: Employment. Jindal:BeiGene: Employment. Sahasranaman:BeiGene: Employment, Equity Ownership.

637 Clinical Prediction Model and Decision Support Tool for Ustekinumab in Crohn's Disease

INTRODUCTION: Identifying predictors of response to treatment with ustekinumab (UST) may improve therapeutic decisions. We created a clinical decision support tool (CDST) for UST therapy in active Crohn's disease (CD). METHODS: Patients from the UNITI trials were included if they received IV UST induction and SQ UST maintenance irrespective of Week 8 response status (derivation set; n = 781). Cox proportional hazard analyses were used to identify baseline factors associated with clinical remission (CDAI 150) by Week 16. The final model was transformed into a CDST and patients were stratified into 3 response probability groups (low, intermediate, high). Secondary analyses were performed to assess the ability of the CDST to predict exposure-efficacy relationships as measured by reduction in CDAI from baseline and differences in trough UST concentrations at weeks 8 and 16. RESULTS: In the derivation analysis, baseline albumin g/L (HR 1.041, 95% CI 1.019–1.063), no prior smoking history (HR 1.233, 95% CI 0.995–1.527), absence of baseline actively draining fistula (HR 1.330, 95% CI 0.906–1.952), absence of prior bowel surgery (HR 1.425, 95% CI 1.140–1.781), and absence of prior exposure to tumor necrosis factor antagonist (HR 1.591, 95% CI 1.214–1.900), were associated with achieving clinical remission by Week 16 of UST therapy. Rates of clinical remission at weeks 3, 6, 8, and 16 were significantly higher in the high probability group versus the intermediate and low probability groups (Table 1). The high probability group had a significantly greater reduction from baseline in CDAI compared to the intermediate and low probability groups at week 8 (high vs. intermediate 94 vs. 54 P &lt; 0.0001; high vs. low 94 vs. 40, P &lt; 0.0001) and week 16 (high vs. intermediate 155 vs. 112 P &lt; 0.0001; high vs. low 155 vs. 84, P &lt; 0.0001). The high probability group had significantly higher trough UST concentrations compared to the intermediate and low probability groups at week 8 (high vs. intermediate 5.2 vs. 3.6 μg/mL P = 0.052; high vs. low 5.2 vs. 2.2 μg/mL, P &lt; 0.0001) and week 16 (high vs. intermediate 2.9 vs. 2.1 μg/mL P = 0.0053; high vs. low 2.9 vs. 1.2 μg/mL, P &lt; 0.0001). CONCLUSION: Predictors of response to UST were identified and successfully modelled into a CDST which can stratify the probability of achieving early clinical remission and rapidity in onset of action in individual CD patients. A statistically significant relationship between UST trough concentrations, probability groups, and efficacy was observed.