Average Cmax Research Articles

Average Slope vs. Cmax: Which Truly Reflects the Drug-Absorption Rate?

Despite ongoing concerns, the primary metric utilized in bioequivalence studies to quantify absorption rate remains the maximum plasma concentration (Cmax). To more accurately depict absorption rate, the concept of “average slope” (AS) has been recently introduced. The objective of this study is to elucidate and compare the characteristics of AS and Cmax in their representation of the drug-absorption rate. For this purpose, an investigation was conducted on five drugs (nintedanib, methylphenidate, nitrofurantoin, lisdexamfetamine, and theophylline) with different absorption and disposition kinetics. The properties of AS and Cmax, as well as their correlations with other pharmacokinetic parameters, were assessed using supervised and unsupervised machine-learning algorithms, namely principal component analysis, random forest, hierarchical cluster analysis, and artificial neural networks. This study showed that, regardless of the absorption kinetics and across every ML algorithm, AS was more sensitive in reflecting the absorption rate compared to Cmax. In all drugs and methods of analysis, AS demonstrated significantly superior performance in expressing the absorption rate compared to Cmax. The joint use of different techniques complemented each other and verified the findings. Moreover, AS can be easily calculated and has the appropriate units and properties to be used as a metric to express the absorption rate in bioequivalence studies. The adoption of AS by regulatory authorities, as an absorption-rate metric, could significantly improve the accuracy and reliability of BE assessments. Overall, this study focused on addressing the longstanding problem of finding an appropriate absorption-rate metric by demonstrating the desirable properties of AS.

Abstract PO2-27-01: TFX06, a next-generation oral CERAN/SERD, shows favorable safety and PK profile, extracranial and intracranial efficacy in patients with ER+/HER2- breast cancer: Preliminary results from a phase 1/2 first-in-human trial

Abstract Aims: TFX06 is an investigational oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) (Wu J, et al., 2023 AACR annual meeting). A Phase 1/2, multicenter, open-label dose-escalation and dose-expansion study (CTR20230789) was initiated in China to evaluate TFX06 in previously heavily treated patients with ER+/HER2- locally advanced and/or metastatic breast cancer. The primary objectives were to assess safety and tolerability, recommended Phase 2 dose (RP2D), and pharmacokinetics (PK). Methods: A 3+3 dose-escalation design was implemented. TFX06 tablets were orally administered at 60 mg/100 mg daily for 28 days of treatment cycle until disease progression or intolerant to TFX06. As of the cut-off date (Sept. 15, 2023), the Phase 1 study enrolled five patients with Stage IV diseases with distant metastases. Three were treated with TFX06 at 60 mg, the starting dose and two at the next dose level of 100 mg. Median age of patients were 50 years (39-65) with a ECOG score of 0-1. Two out of five patients carried estrogen receptor 1 (ESR1) mutations (ctDNA). Prior anticancer treatments included one or two lines of endocrine therapies, including fulvestrant, and/or one or two lines of chemotherapies. Clinical responses by investigator according to RECIST v1.1 were performed every two cycles to explore preliminary efficacy. Results: Three patients in 60 mg and one in 100 mg dose cohorts completed dose-limiting toxicity (DLT) observation period. No DLT observed. All treatment related adverse events (TRAEs) were grade 1-2 in severity, including nausea, drowsiness, decreases in WBC and neutrophils, and anemia. Analyses of plasma concentrations of TFX06 in all three patients receiving 60 mg revealed a similar PK profile with small variations in Cmax. The average steady-state Cmax and Cmin of TFX06 were 101 ng/mL and 65 ng/mL, respectively, and the Cmax of TFX06 was approximately 4-fold higher than that of fulvestrant administered intramuscularly at 500 mg in clinic (28 ng/mL). Two patients in the 60 mg cohort were evaluable for response assessment. One patient discontinued due to progressive disease (PD) after two cycles of treatment. This patient experienced a 17.1% decrease in target lesions in the lung; however, new metastases to bone observed. The other patient who carried ESR1 D538G mutation showed a decrease of 91% in ESR1 mutation burden 8 days after treatment, and a decrease of 34.2% in target lesions (partial response, PR), including a substantial shrinkage of 78.6% in the brain lesion (target lesion), as well as complete responses (CR) of non-target lesions in lung after 4 cycles of treatment. This patient remains on the study as of the cut-off date. Conclusions: Based on the preliminary results, oral administration of TFX06 at 60 or 100 mg once daily had favorable safety and PK profiles. TRAEs, such as gastrointestinal toxicities, bradycardia, and visual disturbances were not observed. Pleasingly, TFX06 demonstrated early extracranial and intracranial antitumor activity (PR) in a patient with a brain metastasis. Citation Format: Zhaojian Fu, Zhiye Zhang, Jia Song, Yang Chen, Douglas Fang, Wei Sha, Jian Zhang, Charles Ding. TFX06, a next-generation oral CERAN/SERD, shows favorable safety and PK profile, extracranial and intracranial efficacy in patients with ER+/HER2- breast cancer: Preliminary results from a phase 1/2 first-in-human trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-01.

Abstract CT111: Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial

Abstract Background NXP800 is an oral, small molecule that activates the integrated stress response through activation of the kinase GCN2. The drug causes growth inhibition and regression in various preclinical models, including ARID1A mutated ovarian and endometrial xenograft and cholangiocarcinoma PDX models. Methods We describe results of the dose-defining dose escalation cohort and the toxicity-pharmacokinetics and pharmacodynamic evaluation in a first-in-human phase I trial of NXP800. Dose escalation was guided by a Bayesian modified continual reassessment method that targeted a dose-limiting toxicity DLT probability (DLTp) closest to 30% but <33%. Toxicity was assessed using NCI.CTC.V5. Detailed sampling of blood for pharmacokinetic analysis and blood for mRNA and protein analysis in peripheral blood mononuclear cells was conducted on C1D-3 to -7 (run in prior to continuous dosing) and C2D1. Two schedules (once per day [QD] and twice per day [BID] and a dose range of 50 to 150 mg/day were evaluated. Results Eighteen patients were treated: at baseline, the median age was 65 years (range 42-77), 9 (50%) were female and 14/18 (78%) had an ECOG score of 1. The most common treatment emergent adverse events (more than 20% of patients) were nausea, vomiting, diarrhea, fatigue, decreased appetite, AST increase and thrombocytopenia. All these side effects were grade 1-2 except grade 3 nausea and grade 3 diarrhea reported in one patient each and grade 3 thrombocytopenia in 2 patients. The MTD for the QD schedule was 100 mg (DLTp=26%), no doses in the BID schedule had estimated DLTp of <33%. The average Cmax at 50 mg and 75 mg OD was 190 nM and 384 nM during the run-in and 495 nM and 656 nM in cycle 2 reached by 3 hours. ATF4 protein in PBMCs was elevated in 57% and 80% of patients during run in and Cycle 2 respectively, 6 hours after 50 mg and 75 mg treatment. The mRNA biomarkers in blood most consistently elevated included ATF4 transcriptional targets NUPR1, ULBP1 and TRIB3 at 2 - 24 hours after 50 mg and 75 mg treatment. Further, mRNA levels for these biomarkers were elevated in post-treatment biopsy samples in one of the two patients tested. It is envisaged that NXP800 will need to be dosed continuously and although the protocol defined MTD at 28 days at 100 mg QD, it was decided to take a dose of range of 50 mg and 75 mg OD which caused biomarker modulation, forward for further evaluation. Conclusions A tolerable dose/schedule of continuous dosing of NXP800 has been established with biomarker modulation in blood. Patients will be randomized to two dose levels 50 and 75 mg/day in a QD schedule to evaluate response in a population of ARID1A mutated, platinum-resistant, clear cell ovarian cancer (NCT05226507). Citation Format: Simon Pacey, Ching Leung, Simon Rodney, Ana Filipa Palma DosReis, Ruth Ruddle, Matthew Tall, Karen Swales, Robert te Poele, Paul Workman, Diane Marsolini, Megan Sardone, Enrique Poradosu, Shay Shemesh, Udai Banerji. Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT111.

Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO. Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax and absolute and percent changes in CAC score from baseline to week 52. Results: Among evaluable patients receiving placebo (n = 15), 300mg (n = 20), or 600mg (n = 20), average Cmax across visits was not quantifiable (<0.76μM), 15μM, and 46μM, respectively. These results suggest a more-than-proportional increase, without accumulation, with a Cmax ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple Emax models described 80% maximal effect at exposures >21.9µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32µM). Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier NCT02966028.

Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).

625 Background: Erdafitinib (E) is a treatment option in mUCpatients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved as a single agent to treat mUC patients following prior PBC and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients. Retrospective studies suggest that the activity of EV is not compromised by FGFR2/3 GAs. E and EV have different mechanisms of activity, and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination E + EV, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR2/3 GAs. Methods: This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination E + EV evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after PBC and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of EV at dose levels of 1 mg/kg and 1.25 mg/kg in combination with E at 8 mg/day as shown in the table. Preliminary safety, PK, and efficacy data for Dose Level (DL) 1 and 2 are presented in this abstract. Results: As of data cutoff, based on 3+3 design, total 8 patients are enrolled and finished dose limiting toxicity (DLT) period (1st cycle). Six patients were enrolled in DL1 with 1 DLT (skin rash) and 2 patients in DL2. The most common treatment-related adverse events (TRAE) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAE included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 subjects in DL1. The average steady-state Cmin of E and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 8 patients are evaluable for response, and best response is partial response in all. Detailed safety and additional efficacy data will be presented. Conclusions: Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153 . [Table: see text]

Prospective Pharmacokinetic Evaluation of Venetoclax (VEN) in AML Demonstrates Significant and Variable Drug Interactions with Azole Antifungals That Increase Ven Exposure, Reduce Clearance, and Necessitate Re-Evaluation of Dose Adjustments

Background: Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC) is the standard of care for the treatment of newly diagnosed AML in pts aged ≥ 75 yrs. or unfit for intensive chemotherapy. While considered low-intensity, myelosuppression is universal, leading to increased rates of infection in the setting of neutropenia. Antifungal prophylaxis during induction has significantly lowered treatment-related mortality (TRM) attributed to invasive fungal infections (Cornely et al, 2007). Azole antifungals, the treatment of choice, pose significant drug-drug interactions through inhibition of CYP3A4 and p-glycoprotein (P-gp), both responsible for VEN metabolism and clearance. This interaction alters VEN pharmacokinetics (PK), increases its exposure, and therefore requires substantial dose adjustments (Agarwal et al, 2017). We previously showed that dose adjusted VEN plus HMA when used concomitantly with azoles retains efficacy, but still resulted in prolonged myelosuppression (Rausch et al, 2022). Little real-world PK data exists to confirm whether the recommended dose adjustments are appropriate or require further refinement. Methods: Pharmacokinetic analysis was conducted during the induction cycle of the phase II study of cladribine plus LDAC and VEN as previously described (Kadia et al, 2022). VEN was administered on days 1-21 during induction and was dose-adjusted to either 100 mg (later amended to 50 mg), 100 mg, or 400 mg daily when used with posaconazole (posa), voriconazole (vori), or caspofungin (caspo), respectively. Dose adjustments were based on package insert recommendations. Prior to amendment, VEN 100 mg was administered with posa based on previously published PK analysis suggesting a 75% dose reduction of VEN with concomitant posa (Agarwal et al, 2017). Steady state VEN PK analysis was conducted on day 8 and trough levels were collected on days 12 and 16 of cycle 1. Levels obtained with concomitant caspo served as a reference level, assuming no significant interaction between VEN and caspo. VEN levels were analyzed via an institutionally developed liquid chromatography coupled mass spectrometry (LCMS) assay and PK analysis was conducted via non-compartmental method using WinOnlin. Results: Forty patients, median age 68 (range, 61-78), were included for pharmacokinetic analysis. Average VEN AUC (area under the exposure) and Cmax (maximum observed plasma concentration) was higher with concomitant vori or posa than with caspo regardless of dose adjustments. Posa in combination with VEN 100 mg increased average AUC by 103% and Cmax by 63%. Vori with VEN 100 mg increased AUC and Cmax by 77% and 43%, respectively. Among the 3 groups, posa with VEN 50 mg resulted in a VEN AUC and Cmax most similar to that observed with caspo and VEN 400 mg. Concomitant posa delayed VEN clearance by 74% with VEN 50 mg and 79% with VEN 100 mg. As a result, the accumulation index observed with posa was 12.5 + 19.98 with VEN 100 mg, 9.2 + 17.5 with VEN 50 mg, and 3.7 + 1.92 with vori, compared to 1.7 + 0.5 with caspo. Although there was interpatient variability in VEN trough levels, we observed consistent intra-patient trough levels. In addition, significant correlation between VEN AUC and VEN trough levels (p = 1 x 10 -4, r 2 = 0.89) was observed. Conclusions: Despite dose adjustments, VEN AUC is significantly higher among pts receiving azole antifungals compared to those receiving caspo. Posa resulted in more potent inhibition of VEN clearance and greater accumulation compared to vori, despite both agents considered strong CYP3A4 inhibitors. This may be a result of the dual inhibitory effect of posa on both CYP3A4 and P-gp activity or more potent inhibition of CYP3A4. Based on PK evaluation, our data suggest VEN 50 mg with concomitant posa provides more similar drug exposure to VEN 400 mg and may be more appropriate than 70 mg or 100 mg in this setting. Given the high accumulation index observed with posa, PK analyses during cycle 2 are ongoing. While there is inter-patient variability in VEN PK, intra-patient trough levels are consistent, correlate well with VEN AUC, and could be used for therapeutic drug monitoring.

1701. Pharmacokinetics in Subjects with Renal Impairment in a Contezolid Complicated Skin and Soft Tissue Infection Phase 3 Clinical Trial

Abstract Background Contezolid (CZD; MRX-I) is a novel oral (PO) oxazolidinone with potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enteroccocus (VRE). In a Phase 3 (Ph3) complicated skin and soft tissue infections (cSSTI) clinical trial (MRX-I-06), 719 subjects were randomized to either CZD 800 mg PO q12h or linezolid (LZD) 600 mg PO q12h with a treatment duration of 7-14 days in both groups. CZD was demonstrated to be noninferior to LZD for the primary efficacy outcome, and overall safety assessments were comparable to LZD. The most common treatment emergent adverse events (TEAEs) in both the CZD and LZD groups were gastrointestinal; however, hematologic laboratory abnormalities and TEAEs were less common with CZD. In June 2021, CZD was approved in China for cSSTI. Sequential therapy with intravenous contezolid acefosamil (CZA; double prodrug of CZD) followed by CZD PO is being evaluated in global Ph3 diabetic foot infection (DFI) and acute bacterial skin and skin structure infection (ABSSSI) clinical trials. Because patients with diabetes commonly have diminished kidney function, pharmacokinetics (PK) in renally impaired subjects were evaluated in MRX-I-06. Methods In MRX-I-06, subjects enrolled included those with estimated creatinine clearance (CLcr) of 60 to &amp;lt; 90 mL/min (mild impairment) and 30 to &amp;lt; 60 mL/min (moderate impairment); no dose adjustments were made for renal status. In a subset of the CZD group, PK was evaluated for subjects with no (CLcr ≥90 mL/min), mild, and moderate renal impairment. Results The CZD PK subset had 63 subjects, of which 19 had renal impairment (18 mild, 1 moderate). CZD subjects with CLcr above and below 90 mL/min had similar PK values, and CLcr was not a significant covariate (below are means ± SD). There was no indication that the variability in CL/F or in AUC was larger due to renal impairment, and the average AUC and Cmax were comparable between subjects with renal impairment and those with normal renal function. Conclusion In a Ph3 cSSTI clinical trial, PK in renally impaired subjects who received CZD appeared similar to those without dysfunction, supporting current Ph3 global DFI and ABSSSI studies with CZD and CZA which will enroll subjects with reduced kidney function. Disclosures Edward Fang, MD, MicuRx Pharmaceuticals Inc: Employee Huahui Yang, MS, MicuRx Pharmaceuticals Inc: Employee.

Phase IIa Study of Adding Itacitinib to Tacrolimus/Sirolimus Gvhd Prophylaxis after Fludarabine/Melphalan-Based Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, Myelodysplastic Syndrome, or Myelofibrosis

Graft-versus-host disease (GVHD) is the primary cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Itacitinib is a novel, potent, and selective Janus kinases-1 (JAK1) inhibitor that has shown activity in treatment of acute and chronic GVHD. We hypothesized that adding Itacitinib to the standard tacrolimus/sirolimus GVHD prophylaxis is safe and can potentially improve GVHD-free, relapse-free survival (GRFS). Here, we are reporting outcomes of our single arm, single center phase 2a study (NCT04339101) investigating the safety and efficacy of itacitinib administration in patients with acute leukemias, myelodysplastic syndrome (MDS), or myelofibrosis (MF) who underwent PBSC-HCT from a matched donor. Patients received fludarabine (125 mg/m2) and melphalan (140 mg/m2 or 100 mg/m2 for patients ≥70 years) as reduced intensity conditioning. GVHD prophylaxis was sirolimus/tacrolimus (target levels: 5-10ng/ml for both), with itacitinib at 200 mg/day starting from day -3 pre-HCT and continued until day +100. (Figure 1a) Our primary objective was to investigate the safety of itacitinib (Safety lead-in segment; n=6) and estimate 1-year GRFS. Ultimately a total of 59 patients were treated with itacitinib at 200 mg/day dose. Primary endpoint for the safety lead-in segment was toxicity; scored on both the Bearman and NCI CTCAEv5.0 scales. Primary endpoint for the expansion segment was 1-year GRFS. Key secondary endpoints included grade 2-4 acute GVHD, engraftment, infection, overall survival (OS), progression-free survival (PFS), NRM, relapse, chronic GVHD, and itacitinib pharmacokinetics (PK). The enrollment goal was 59 including 6 in the safety lead-in to estimate GRFS at 45% with precision of 0.13. We completed the enrollment (n=59; 36 males [61%] and 23 [39%] females) in May 2022. Median age at the time of HCT was 63 years (range: 23-75), with 14 patients being ≥70 years old at the time of HCT. Patients received HCT from a matched related (n=22) or unrelated (n=36) donor for acute leukemias (n=38; 64.4%), MDS (n=17; 28.8%), or MF (n=4; 6.8%). HCT-CI was 0 in 37 (62.7%) and 1 in 14 (23.7%) of patients. At the time of this report, 57 patients have completed the 100-day observation. The current report is focused on the early data and endpoints with a median follow up duration of 5.9 months (range: 0.6-12.4). There was no case of protocol-defined unacceptable toxicity in the safety lead-in phase. All 59 patients engrafted with a median time to neutrophil and platelet engraftment of 15 days (range: 11-23) and 16 days (range: 8-80), respectively. There were no deaths in the first 100 days except for one patient who passed due to severe sepsis and resultant multiple organ failure. Grade 3-4 adverse events (by CTCAEv5.0) within 100 days, reported as at least possibly related to itacitinib, were anemia (n=1), febrile neutropenia (n=2), abdominal pain (n=1), lymphocytopenia (n=8), neutropenia (n=1), thrombocytopenia (n=3), leukopenia (n=3), and hypertriglyceremia (n=1). There were 19 microbiologically documented infections during the first 100 days (12 bacterial, 5 viral, and 2 fungal infections). Acute GVHD grade 2-4 and 3-4 were observed in 6 (10%) and 5 (8%) patients, respectively. With the limited follow up duration (5.9 months) and observed events including all-cause mortality (n=9, NRM=6), grade 3-4 acute GVHD (n=5), moderate/severe chronic GVHD (n=2), and disease relapse (n=8), the estimated GRFS at 6-months and 1-year were 0.71 (95%CI: 0.56-0.81) and 0.51 (95%CI: 0.31-0.68), respectively. (Figure 1b) Results of our preliminary PK studies (n=18) showed average itacitinib trough levels between days -2 and +5 of 25.2.6 ± 39.1 nM. Average Cmax, AUC 0-inf, T1/2, and CL/F around the dose on Day +5 were 11362.0 ± 852.9 nM, 4905.6 ± 2422.8 nM x hr, 4.4 ± 1.7 hr, and 90.3 ± 39.6 L/hr (Figure 1c). The measured itacitinib exposure is significantly higher than previously reported results, indicating a potential drug interaction with sirolimus. In conclusion, early results of this phase 2 study indicated that itacitinib (200 mg daily) with tacrolimus/sirolimus GVHD prophylaxis was safe and tolerated with 100% engraftment and low rate of acute GVHD without excessive toxicities. Early survival data including preliminary GRFS are promising. The study follow up is ongoing, and mature clinical data and immune reconstitution analyses will be updated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ibrutinib-Associated Sudden Death in Patients with CLL

INTRODUCTION: Ibrutinib therapy is associated with an increased risk of cardiac arrhythmias. There is currently no standard for cardiac screening or monitoring in patients on ibrutinib and it remains unknown which factors predispose patients to serious or fatal arrhythmias. METHODS: We report a retrospective cohort study of patients with chronic lymphocytic leukemia (CLL) on ibrutinib-based therapies at the NIH Clinical Center from 2012-2022. Electronic medical records were reviewed for cardiac symptoms, cardiac testing, and autopsy reports. Patients with sudden death were analyzed for 41 genes associated with inherited and syndromic conditions involving cardiac arrhythmias (Invitae). Serum concentrations of ibrutinib from stored samples were measured. RESULTS: A total of 131 patients with CLL received ibrutinib-based therapy (128 single-agent ibrutinib and 3 ibrutinib-duvelisib). Five patients (3.82%) had sudden death over an observation period of 624 patient-years. At time of death, 4 patients were receiving ibrutinib monotherapy and 1 was receiving ibrutinib in combination with duvelisib. The median age of sudden death was 62 (range 48-70) and the median duration of ibrutinib treatment at time of death was 21 months (range 0.1-56.2). All patients with sudden death had elevated body mass indices, 4 had pre-existing concurrent hypertension and hyperlipidemia, 2 had cardiac symptoms prior to starting ibrutinib (palpitations, chest pain, dizziness, dyspnea on exertion), and only 1 developed cardiac symptoms while on ibrutinib (palpitations at 33 months). Three patients had documented arrhythmias while on ibrutinib, including 2 with occasional ectopy and bradycardia on resting EKG and 1 with ventricular couplets on exercise stress test. In serum samples collected 0.1-8.1 months prior to death, only 1 patient had an elevated ibrutinib concentration of 278.18 ng/mL, above the expected average Cmax of 190 ng/mL after a 420mg dose of ibrutinib (Advani et al. J Clin Oncol, 2013). Genetic analysis revealed no pathologic variants associated with cardiac arrhythmia genes, but did show 2 different variants of uncertain significance in 2 patients. Autopsies were performed in 3 patients and identified structural cardiac abnormalities in 2 patients: 1 with hypertensive cardiomyopathy and another with cardiovascular dysplasia and fibrotic bundle branches. None of the autopsies showed obstructive coronary artery disease, heart failure, ischemia, embolism, or other apparent cause of sudden death. DISCUSSION: Continuous ibrutinib therapy until disease progression or treatment toxicity is a treatment strategy widely used in CLL. However, limited data are available regarding the relationship between ibrutinib, ventricular arrhythmias, and sudden death. The incidence of sudden death in our study was 801 per 100,000 patient-years, which is similar to a previous estimate of 788 per 100,000 patient-years among ibrutinib-treated patients (Lampson et al. Blood, 2017) and higher than 102 per 100,000 patient-years (95% CI 24-180) in an age-matched cohort (Maruyama et al. BMJ Open, 2012). One patient showed cardiovascular dysplasia and fibrosis at autopsy; interestingly, pre-clinical data in mice showed ibrutinib-induced myocardial fibrosis as a contributing factor to the development of atrial fibrillation (Xiao et al. Circulation, 2020). However, autopsies could not identify a common cause of death between the 3 patients. CONCLUSION: Early identification of cardiac arrhythmias on treatment may prevent serious arrhythmias and sudden death. Recently introduced guidance in the ibrutinib prescribing information describes dose reductions or discontinuation at the first occurrence of grade 2 or higher cardiac failure or arrhythmia in patients with CLL. Further research is warranted to identify risk mitigation strategies.

A preliminary report on bioavailability of Ayurvedic Gold Bhasma with four different accompanying media [anupana

Background: Gold bhasma [Swarnabhasma] is a ancient Ayurvedic medicine used for rejuvenation and longevity. This is a preliminary attempt to study the bioavailability of this medicine. Objectives: It was aimed to estimate comparative bioavailability of gold bhasma up to five hours after oral dose with four different anupana. Materials and methods: In this in vivo study, 30 healthy human participants were allocated randomly into five groups having six individuals each. Gold bhasma in 30 mg dose was administered orally with four different anupana viz honey [2.5 gm], black pepper-ghee combination [250 mg and 2.5 gm respectively], lactose [250 mg], glucose [250 mg], and plain to participants in each group. Blood samples were collected at 0, 1, 3 and 5 hours after dose. Gold levels in blood were assessed by inductively coupled plasma mass spectrometry [ICP-MS]. Results: Gold levels in all blood samples were in traces. Average Cmax was 0.002333 microgram of gold per liter and Tmax was at 3 hours for honey anupana, showing maximum Cmax among all groups. Conclusions: Preliminary results indicate that bioavailability of gold from gold bhasma may be less than 0.01 % upto first five hours. Gold bhasma mixed with honey resulted in attainment of maximum Cmax. It is evident that accompanying media [anupana] play an important role in absorption of gold bhasma.

Abstract 1370: ADME and toxicology profiles of first-in-class DRD2/ClpP-targeted imipridone ONC201

Abstract Imipridone ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients with once weekly dosing. We evaluated the toxicology, absorption, distribution, metabolism and excretion of ONC201 in animals. Repeat-dose 28-day studies with weekly oral ONC201 in rats and dogs revealed NOAELs (75 and 60 mg/kg, respectively) that represent higher dose levels compared to the 625 mg clinical dose. Genotoxicity (AMES, in vitro and in vivo micronucleus assays) assays demonstrated that ONC201 is not mutagenic at exposures above the RP2D and 2µM average Cmax in patients. The 3T3 neural red uptake assay showed ONC201 is not a phototoxin (photo-irritant factor 1.1). In embryofetal development studies, ONC201 did not lead to maternal effects in rats or rabbits and caused fetal malformations in 3/61 rabbit fetuses with daily dosing (from gestation day 7-17 or 19) at 62.5 and 25 mg/kg, respectively. A quantitative whole-body autoradiography study conducted in rats with one dose of [14C]-ONC201 showed rapidly tissue distribution peaking at 1h in most tissues and exhibiting a plasma terminal half-life of 5.6h. The endocrine, metabolic/excretory, ocular and GI tract tissues contained the highest distribution of [14C]ONC201. [14C]-ONC201 was distributed evenly across CNS substructures, including the midline region. Consistent with the uniform distribution, ONC201 displayed high permeability (23-31×10-6 cm/s, 7-700 μM) and was not a substrate of efflux transporters in Caco-2 cells (efflux ratio 0.46-0.79). ONC201 exerted inhibitory potential on MDR1- and BCRP-mediated transport at 200μM. Clinical trials with ONC201 restrict use of concomitant medications that induce or inhibit CYP enzymes, but several supportive medications can affect these enzymes. In vitro studies revealed that ONC201 is not an inducer of 7 major human CYP enzymes but does inhibit and is a substrate of CYP 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 (IC50 20-90µM). Analysis of dexamethasone, a known inducer of CYP3A4, did not show a correlation between baseline dose level and ONC201 plasma concentrations in H3 K27M-mutant glioma patients (n=22). Metabolic profiling in human hepatocytes revealed only one metabolite, ONC207, that was &amp;gt;10% in abundance. ONC207 did not achieve an IC50 in cancer cell viability and DRD2 antagonism assays. Assaying by LC-MS/MS of plasma samples obtained from ONC201-treated H3 K27M-mutant glioma patients (n=20) confirmed the presence of ONC207 as the major metabolite. A mass balance study conducted in rats with one dose of [14C]-ONC201 showed that the main route of excretion was biliary (61.18%) via the feces (69.78%), with urine (24.99%) also contributing to overall recovery. Together, these data inform the administration of ONC201 to advanced cancer patients who often require a range of comedications and comorbidities. Citation Format: Sara Morrow, Rohinton Tarapore, Ailan Guo, Magdalena Nej, Yunlan Fang, Gina Theerman, Leah Lake, Martin Stogniew, Varun V. Prabhu, Joshua E. Allen. ADME and toxicology profiles of first-in-class DRD2/ClpP-targeted imipridone ONC201 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1370.

Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy.

When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal β-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1μg/mL (CV: 0.32) and 8.7 μg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 μg×h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h×kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg×h/mL, respectively) were lower than and statistically significantly different from (p<0.001 and p=0.001, respectively) those expected for healthy volunteers. Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.

Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial.

SummaryBackgroundCurrent rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts—cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics.MethodsPhase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR–European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0–6 h (AUC0–6) were measured. This study is registered with ISRCTN, ISRCTN36667085.FindingsBetween Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18–0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0–6 were two-times higher in participants developing dose-limiting toxicities.InterpretationThe maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial.FundingUK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.

Conversion of primary tropical rainforest into rubber plantation degrades the hydrological functions of forest litter: Insights from experimental study

Plant litter is an important component of forest ecosystems and has a key role in reducing soil and water loss. This study evaluated the effect of land use change on rainfall interception and other hydrological processes associated with the litter layer in the tropical region of Southwest China, where large areas of tropical rainforest (TR) have been converted into rubber monoculture (RM) in the past decades. Two litter types from the TR and RM were selected to determine the maximum water storage capacity (S), maximum and minimum interception storage capacities (i.e., Cmax and Cmin, respectively) and moisture dynamics under four litter masses and five simulated rainfall intensities. Results showed that the distribution of litter layer in the RM had a higher spatial variability than that in the TR. The average litter thickness in the TR and RM was 6.42 and 4.43 cm, respectively, and the S value of the litter layer in the TR and RM was 1.44 and 1.03 mm, respectively. Linear relationships among litter thickness, S, and litter mass were observed. The average Cmax and Cmin in the TR were respectively 1.25 and 1.30 times greater than that in the RM. Significant positive relationships among litter mass, rainfall intensity, and interception storage capacity were observed, indicating that litter mass and rainfall intensity played a critical role in determining rainfall interception of the litter layer. TR litter from mixed species had larger leaf surface area and higher water affinity, which resulted in 1.38 times greater litter interception (12.32%) than RM litter (8.96%). These results indicated that the conversion of TR into RM considerably weakened the hydrological functions of forest litter, such as water storage capacity and rainfall interception, and possibly subsequent erosion control. Introducing native rainforest species into rubber plantations can help improve the litter input and the hydrological attributes of forest litter.

Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma.

Purpose Axitinib is an orally active multikinase inhibitor currently used to treat patients with metastatic renal cell carcinoma (RCC). This study examined the pharmacokinetics of axitinib and the relationship between peak drug concentration (Cmax) and clinical outcomes in real-world practice. Methods Twenty patients with metastatic RCC treated with axitinib monotherapy were enrolled. Post-dose (1-4h) blood samples were obtained, and axitinib Cmax in plasma was measured by liquid chromatography-tandem mass spectrometry. Efficacy endpoints were best overall response (per RECIST 1.1) and progression-free survival (PFS). The safety endpoint was the cumulative incidence of dose-limiting toxicities (DLTs). Results Large inter- and intra-individual variability in dose-adjusted Cmax was observed (0.02-11.2ng/mL/mg). Axitinib absorption was significantly influenced by glucuronidation activity (P = 0.040). Cmax at steady state was significantly higher in responders than in non-responders (P = 0.013). The optimal Cmax cutoff to predict a clinical response was 12.4ng/mL. The median PFS was significantly longer in patients who achieved an average steady state Cmax above the threshold than in those who did not (799 vs. 336days; P = 0.047). The cumulative incidence of DLTs was significantly higher in patients with Cmax ≥ 40.2ng/mL than in other patients (sub-hazard ratio, 4.13; 95% confidence interval, 1.27-13.5; P = 0.019). Conclusions The potential therapeutic window of axitinib Cmax in metastatic RCC was estimated at 12.4-40.2ng/mL. Pharmacokinetically guided dose titration using therapeutic drug monitoring may improve the efficacy and safety of axitinib, warranting further investigation in a larger patient population.

Development and Validation of Montelukast with Grape/Licorice Juices and its Application to Pharmacokinetic Studies by LC/MS

A simple, rapid and sensitive simultaneous method for validation and determination of Montelukast in rat plasma in the presence of grape and licorice juices has been done by using High Performance Liquid Chromatography–Mass Spectrometry (HPLC/MS). A mixture of (77.5 % methanol, 22.5 % of 0.2% FA in water) was used as a mobile phase, ACE 5 C8 column (50 X 2.1 mm, 5μ), and a flow rate of 0.1 ml/min were used, the auto-sampler injection volume was 5 microliters, and candesartan was used as an internal standard. According to the result obtained, the precision of predicted measurements for Montelukast was good (mean CV % 0.05) of grape on Montelukast Cmax (163.492 ng/ml ±113.27). Neither licorice gives significant decrease in the Montelukast Cmax (143.861ng/ml ±54.52), its only delay the average Montelukast Cmax to half an hour. Even for the AUC, there were no significant difference between Montelukast alone and Montelukast with grape, and Montelukast with licorice (P>0.05). The kinetic data shows that Montelukast plasma level was the same with both combination of Montelukast and grape, and Montelukast and licorice.

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD &gt; 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD &gt; 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development.

A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases—dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp® physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average Cmax and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles.

On the usefulness of compendial setups and tiny-TIM system in evaluating the in vivo performance of oral drug products with various release profiles in the fasted state: Case example sodium salt of A6197

We evaluated the usefulness of quality control dissolution data collected with compendial Apparatus I and II, biorelevant dissolution data collected with compendial apparatus IV, and bioaccessibility data collected with the non-compendial tiny-TIM system in screening modified release formulations during the development of BCS Class I compounds using a Boehringer Ingelheim model experimental compound, A6197. Four products were investigated: an immediate release tablet, an extended release tablet, modified release mini-tablets, and extended release pellets. Data with modified release products collected with the compendial apparatus were evaluated vs. the average intraluminal dissolution estimated after deconvoluting clinical data collected in healthy adults. Data collected with the tiny-TIM system were evaluated vs. the average AUC and Cmax values estimated from the clinical data. Unlike with the quality control data collected with Apparatus I and II, data collected with Apparatus IV data and Level I biorelevant media adequately described the intraluminal dissolution process of the three modified release products. Data deviated less than 10% from the actual average deconvoluted intraluminal dissolution profiles, illustrating the usefulness of Apparatus IV biorelevant data in understanding the intraluminal dissolution process of BCS class I small molecules administered as modified release products in the fasted state. Total bioaccessibility data and maximum bioaccessibility data collected using the tiny-TIM and the immediate release tablet and the three modified release drug products correctly reproduced the ranking of A6197 AUC values (R2 = 0.989) and Cmax values (R2 = 0.962), respectively, illustrating tiny-TIM as a useful system for formulation selection of BCS class I small molecules administered in the fasted state.

Compression-based injury variables from chestbands in far-side impact THOR sled tests

Objective: This study seeks to determine compression (Cmax) and compression-related injury variables (velocity and viscous injury criterion: Vmax and VCmax) from chestband data in pure lateral and oblique far-side impact sled tests.Methods: The 3-point belt–restrained mid-sized male Test Device for Human Occupant Restraint (THOR) dummy was placed on a buck and subjected to side impacts with and without center-mounted airbags. The change in velocity was 8.3 m/s for all conditions. Two chestbands were routed around the outer circumference of the THOR at the levels of the third and sixth ribs. Maximum chest deflections were computed using strain gauge signals from the chestbands and their temporal contours. Three methods were used to determine deflection metrics. The first method paralleled methods used in previously published human cadaver studies; the second method used the actual anchor point location and actual alignment of the dummy’s internal sensors; and the third method used the anchor location of the internal sensor but determined the sensor’s locations on the contour confining to the aspect of the sensor. These 3 approaches are abbreviated as the SD, ID, and TD variables. The injury variables Cmax, Vmax, and VCmax were determined according to accepted procedures. Their peak magnitudes were extracted and an evaluation of their accuracy was made based on the SD method.Results: The average SD-based Cmax magnitudes for the upper and lower chest levels were 0.12 and 0.17 m/s, the Vmax magnitudes were 5.3 and 1.8 m/s, and the VCmax magnitudes were 0.24 and 0.15 m/s, respectively. Other data are given for all variables at the 2 levels of the thorax in the body of this paper. The ID-based peak variables were the lowest, and this observation was true regardless of the aspect, right or left side. In contrast, the SD method produced the greatest magnitudes of the variables. The VCmax variable had the greatest normalized difference among all 3 injury variables.Conclusions: Though the present study is limited in scope, the predetermined placement of the internal sensors in the THOR dummy underpredicted chest deflection-related injury variables, and the viscous criterion was the least reliable variable in these lateral and oblique far-side impact sled tests.