PK Parameters Research Articles

Pharmacokinetic-Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity.

This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

Pharmacokinetic/pharmacodynamic relationships of enrofloxacin against Klebsiella pneumoniae in an in vivo infection model in young chicks

Klebsiella pneumoniae is a serious pathogenic bacterium that poses a significant threat to young poultry and the cause of significant chick mortality and economic loss. We investigated the therapeutic efficacy of enrofloxacin in treating K. pneumoniae infections in chicks and employed an in vivo pharmacokinetic/pharmacodynamic (PK/PD) model. In vivo efficacy was evaluated using six multiple-dose groups (oral administration once a day for three days) and two single-dose groups (oral administration once only). The PK and PD parameters of plasma and lung were analyzed using PK/PD fitting analysis. K. pneumoniae administered intratracheally (108 CFU/mL in 0.4 mL saline) was used to establish a model for pulmonary infection. The plasma protein binding of enrofloxacin was 20.18%. Enrofloxacin displayed T1/2β values of 4.78 ± 0.69 h and 4.78 ± 1.02 h in plasma and lung of infected chicks, respectively. When the dosage in the multiple-dose group was ≥ 20 mg/kg, bactericidal activity was found and complete eradication was not achieved when the dosage was ≤ 40 mg/kg. When TMSW was set at 20%, the calculated dosage and bacterial reduction (E) based on plasma free drug data were 4.03 mg/kg and -1.982 Log10 CFU/mL, respectively. In the calculation of PK/PD parameters for reducing 3 log10 CFU/mL and using Cmax/MIC, AUC72h/MIC and TMSW of free drug in plasma values at 9.479, 379.691 and 44.395%, respectively, the value of AUC72h/MIC based on the concentration of drug in lung was 530.800. According to the fitting correlation R2, the PK/PD fitting results of free drug in plasma were better. The corresponding enrofloxacin dosage for AUC72h/MIC of the plasma free drug concentration was 14.16 mg/kg. The administration regimen corresponding to these dosages was once daily for 3 days. This dosage regimen (14.16 mg/kg) was relatively high compared to the clinically recommended dosage in China (7.5 mg/kg) when treating infections caused by K. pneumoniae with MIC ≥ 0.125 μg/mL, so careful consideration is needed.

Cariprazine Orodispersible Tablet: A New Formulation for Cariprazine.

Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg. This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively. Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC0-72h and Cmax geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% - 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine. The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia.

The association between vancomycin trough concentrations and nephrotoxicity in the paediatric intensive care unit

Objective: To analyze and describe the pharmacokinetic aspects of vancomycin usage in a cohort of critically ill children and to construct a pharmacokinetic model for this population. Method: We conducted an observational study in a pediatric intensive care unit from September 2017 to March 2019. Children receiving vancomycin with at least one serum measurement were included. Variables with a p-value lower than 0.2 in univariate analysis, and biologically plausible for inducing nephrotoxicity and not correlated with other predictors, were incorporated into logistic regression. Additionally, pharmacokinetic modeling was performed using the PMETRICS® package for patients with creatinine clearance (CLCR) > 30 mL/min. Result: The study included 70 children, with an average vancomycin dose of 60 mg/kg/day. Only eleven children achieved vancomycin levels within the target range (15-20 mg/L). No significant differences in doses/mg/kg/day were observed among children above, within, or below the vancomycin target range. In the multivariate model, children above the recommended serum range had an odds ratio of 4.6 [95% CI 1.4 – 17.2] for nephrotoxicity. A pharmacokinetic model was proposed using data from 15 children, estimating PK parameters for CLCR and V as 0.94 L/h and 5.71 L, respectively. Conclusion: Nephrotoxicity was associated with vancomycin plasma concentrations equal to or exceeding 15 mg/L. The developed model enhanced understanding of the drug’s behavior within this population, potentially aiding clinical practice in dose calculations and estimation of the area under the curve – a recommended parameter for vancomycin monitoring.

Pre-clinical Pharmacology and Tolerability Characterization of a Novel KIRxICOS Targeting Bispecific CD8 Treg Modulator

Abstract Here we present an Fc-based bispecific CD8 Treg modulator that binds in cis to inhibitory KIR and ICOS receptors co-expressed by CD8 Treg designed to restore CD8 Treg functions. CD8 Treg dysfunctions include impaired cytotoxicity and insufficient longevity in autoimmune disease affected tissues. The KIRxICOS targeting bispecific molecule selectively enhances CD8 Treg killing, promoting their recruitment to and survival within disease affected tissues. Through in vitro, ex vivo, and in vivo evaluations in humanized mouse models, we assessed binding, specificity, and function of the KIRxICOS CD8 Treg Modulator, which boosted ICOS signaling in KIR-expressing CD8 Treg, without activating immune cells expressing only ICOS. It extended survival and reduced disease score in a humanized acute GvHD model, marked by a reduction of activated CD4 T cells and an increase of CD8 Treg. In antigen stimulated tissues, the KIRxICOS CD8 Treg modulator reduced CD4 derived proinflammatory cytokines and epithelial cell death. In vivo, the KIRxICOS molecule demonstrated antibody-like PK parameters. Repeat dose studies in huNSG(IL15Tg) mice indicated good tolerability without terminal toxicity or induction of proinflammatory serum cytokines. The evaluation of binding, impact on immune cell phenotypes, and pharmacology revealed immune cell binding without activation. Our preclinical data supports development of the KIRxICOS CD8 Treg modulator as a therapeutic in autoimmune disease.

Population pharmacokinetic analysis for dose regimen optimization of vancomycin in Southern Chinese children.

Changes in physiological factors may result in large pharmacokineticvariability of vancomycin in pediatric patients, thereby leading to either supratherapeutic or subtherapeutic exposure and potentially affecting clinical outcomes. This study set out to characterize the disposition of vancomycin, quantify the exposure target and establish an optimal dosage regimen among the Southern Chinese pediatric population. Routine therapeutic drug monitoring data of 453 patients were available. We performed a retrospective population pharmacokineticanalysis of hospitalized children prescribed intravenous vancomycin using NONMEM® software. A one-compartment PPK model of vancomycin with body weight and renal functions as covariates based on a cutoff of 2 years old children was proposed in this study. Both internal and external validation showing acceptable and robust predictive performance of the model to estimate PK parameters. The value of area under the curve over 24 h to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 260 was a significant predictor for therapeutic efficacy. Monte Carlo simulations served as a model-informed precision dosing approach and suggested that different optimal dose regimens in various scenarios should be considered rather than flat dosing. The evaluation of vancomycin exposure-efficacy relationship indicated that lower target level of AUC0-24/MIC may be needed to achieve clinical effectiveness in children, which was used to derive the recommended dosing regimen. Further prospective studies will be needed to corroborate and elucidate these results.

Abstract CT064: Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study

Abstract Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison. Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials. TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ] Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [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 CT064.

Abstract CT133: A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in >5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer [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 CT133.

Abstract 5925: Safety, efficacy, pharmacokinetics, and pharmacodynamics of a second generation Irofulven analog CAP-0121 in preclinical cancer models

Abstract Background: Irofulven is a semisynthetic sesquiterpene anticancer agent initially investigated for its unique mechanism of action and potential to overcome resistance observed in other chemotherapeutics. This study investigates the pharmacokinetics and pharmacodynamics of a second generation irofulven analog, CAP-121 (Califia Pharma), and its efficacy and safety in preclinical cancer models relative to irofulven. Methods: 24-hour comprehensive PK was performed at two different intravenous (IV) doses in canines for irofulven (0.2 mg/kg and 1 mg/kg; MTD) and CAP-121 (1 mg/kg and 3 mg/kg). Plasma concentrations were measured by ultra-high performance liquid chromatography multiple reaction monitoring mass spectrometry. PK parameters were determined for both compounds using noncompartmental methods (Phoenix WinNonlin, version 8.4). PK parameters included area under the concentration vs time curve (AUC), maximum observed concentration (Cmax), clearance (CL), volume of distribution (Vd), and elimination half-life (t1/2). Canine platelet and neutrophil counts were measured across 28 days to ascertain the maximum tolerated dose (MTD); platelet count reversibility was also assessed. Mice xenograft models implanted with a drug resistant human ovarian cancer (A2870), or a drug-resistant human metastatic lung cancer (MV522), were dosed with irofulven (9 mg/kg; MTD) and CAP-121 (15, 20, and 25 mg/kg) and resulting tumor mass, % change in body weight, and platelet counts were compared relative to vehicle only. Results: Systemic exposure, CL, Vd, and t1/2 were similar between irofulven and CAP-121 at a 1 mg/kg IV dose. For irofulven, exposure increased approximately proportionally at doses of 0.2 mg/kg and 1 mg/kg. For CAP-121, exposure increased less than proportionally at doses of 1 mg/kg and 3 mg/kg. MTD of CAP-121 was found to be 3-fold higher in canines compared to irofulven as 3-fold more CAP-121 was required to match the platelet reduction with irofulven; platelet nadir was rapidly reversible for CAP-121. Canine nadir platelets were 3-fold higher for CAP-121 vs irofulven at the same dose (1 mg/kg). CAP-121 was superior to irofulven (p < 0.02) with regards to final tumor weights in mice xenograft models, even though MTD was not reached for CAP-121; a change in body weight and platelet loss was not observed for CAP-121 at up 25 mg/kg in mice. Conclusion: The canine PK/PD study of CAP-121 demonstrates that CAP-121 has favorable PK parameters. With regards to in vivo anticancer cytotoxic activity, the two drug-resistant xenograft models confirm the superiority of CAP-121 over irofulven. Together, these findings indicate a wider therapeutic window in humans is expected for CAP-121 compared to irofulven, emphasizing the potential anticancer utility of CAP-121 for solid cancers without prolonged thrombocytopenia. Further investigation in clinical trials is warranted Citation Format: Raymond T. Suhandynata, T K. Nguyen, Venkata R. Kotamraju, Jeremiah D. Momper, Michael J. Kelner. Safety, efficacy, pharmacokinetics, and pharmacodynamics of a second generation Irofulven analog CAP-0121 in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5925.

Abstract 7165: Clinical population pharmacokinetic (popPK) analysis of NBF-006, a novel siRNA inhibitor of glutathione-S-transferase P (GSTP) encapsulated in a lipid nano particle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC)

Abstract GSTP has an important role in detoxification and antioxidative damage response. Additionally, GSTP has a chaperone function that regulates multiple oncogenic pathways such as KRAS and JNK. Since alternative pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a drug product comprised of GSTP siRNA encapsulated within a novel LNP. It is designed to deliver siRNA to localized and metastatic lung tumors. Unlike other well-established drug modalities, there is a general need for increased understanding of the PK of RNA therapeutics. For NBF-006, we present popPK analysis of patients who have undergone treatment in a Phase I (a/b) clinical study. A primary goal of popPK modeling is to identify PK parameters and sources of variability in a population. Other goals include correlating drug exposures with administered doses through identification of predictive covariates in a target population and establishing whether fixed dosing as opposed to weight-based dosing can be utilized in future clinical studies. Ultimately this analysis will help to inform decision-making for dosing regimens in future clinical trial designs and to better predict PK variability across populations. A total of 48 advanced NSCLC (N=38), pancreatic (N=5), or colorectal cancer (N=5) patients received 4 doses (QW) of NBF-006 by infusion at 0.15, 0.3, 0.6, 1.2 or 1.6 mg/kg followed by a 2-week rest period. In all studies, serial blood samples were collected at weeks 1 and 4. Plasma concentrations of siRNA were determined by hybridization ELISA. PopPK analysis was performed to characterize NBF-006 PK and to explore intrinsic and extrinsic covariate effects that could affect NBF-006 exposure. The analysis included 695 quantifiable PK observations. A popPK model with two-compartment disposition and linear elimination adequately described the PK profile of NBF-006. Exploratory data analysis of dose-normalized PK profiles suggested that exposure increased proportionally with increasing dose from 0.15 to 1.6 mg/kg. Little to no apparent accumulation nor exposure reduction was observed between weeks 1 and 4. The impact of individual patient covariates, including body weight, baseline ALT, sex, KRAS mutation, cancer type and race, was assessed on PK parameters. None of the covariates evaluated had a significant effect on NBF-006 clearance or central distribution volume (Vc) in the model. Vc showed a slight positive trend with higher body weight, but was not statistically significant. A popPK model was successfully developed for NBF-006. No covariates were identified that impact NBF-006 exposure. The lack of a relationship of exposure with body weight suggests the potential to use fixed dosing in future clinical studies. Citation Format: Michael P. Hall, Zhihong O'Brien, Xi Chen, Angelean Hendrix, Stacy Brenes-Coto, Sonya Zabludoff. Clinical population pharmacokinetic (popPK) analysis of NBF-006, a novel siRNA inhibitor of glutathione-S-transferase P (GSTP) encapsulated in a lipid nano particle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7165.

Abstract 7162: Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients

Abstract Atezolizumab is an anti-PDL1 approved for treating small cell lung cancer and non-small cell lung cancers. A threshold of 6 µg/ml in plasma has been associated with target engagement with Atezolizumab. The extent to which patients could be overexposed with the standard 1200 mg Q3W flat-dosing remains unknown, but several in silico studies have suggested that flat-dosing with immune checkpoint inhibitors could lead to plasma concentrations far above the necessary levels to be efficacious. Here, we monitored Atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels of Atezolizumab. No patient displayed plasma levels below 6 µg/ml. The results showed that the mean trough level after the first course was 78.3 ± 17 µg/ml, i.e., 13 times above the target concentration associated with target engagement. The overall response rate was 55.5%. Low-grade IRAEs was observed in 37% of patients. No severe immune-related toxicities was observed. On univariate analysis, no relationship was found between exposure metrics of Atezolizumab (i.e., Cmin, Cmax, AUC at the first cycle or during the forthcoming courses) and pharmacodynamic endpoints (i.e., efficacy, toxicity). First-line Atezolizumab treatment and treatment for NSCLC were both significantly associated with efficacy on univariate analysis (p=0.0067 and p=0.0497, respectively), but further multivariate analysis did not confirm this relationship (p=0.2465 and p=0.9981). Smoking status was moderately associated with toxicities on univariate analysis (p=0.03), but this effect was not confirmed on further multivariate analysis (p=0.99). None of the other covariates (i.e., age, sex, NLR, number of metastatic sites, associated chemotherapy) were associated with efficacy or toxicity. Further simulations suggested that the dosing interval could be extended from the standard 21 days (i.e., Q3W) to 49 up to 136 days (mean: 85.7 days, i.e., Q12W dosing), while ensuring plasma levels always above the 6 µg/ml target threshold. This observational, real-world study confirms for the first time in real-world patients that the standard 1200 mg Q3W fixed-dose regimen of Atezolizumab results in significant overexposure in plasma. Of note, this overexposure was not associated with increased side-effects. As plasma levels always exceed pharmacologically active concentrations, the inter-individual variability we observed in PK parameters did not impact efficacy and could not explain differences in response. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy, thus lowering drug-cost in the future. Citation Format: Sophie Marolleau, Alice Mogenet, Mourad Hamimed, Clara Boeri, Laurent Greillier, Joseph Ciccolini. Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7162.

Abstract 7172: Pharmacokinetic/biomarker (PK/BMx) analysis of the toll-like receptor 7 and 8 (TLR7/8) agonist EIK1001 in phase 1 studies in participants (Pts) with solid tumors

Abstract Introduction: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a TLR7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Adults with advanced solid tumors received a range of doses of EIK1001 (QW IV) alone and in combination with pembrolizumab (200 mg Q3W; NCT03486301) or atezolizumab (1200 mg Q3W; NCT04196530) in Phase 1 studies (n=128). PK samples were collected on Cycle 1 Day 1 (C1D1) and C1D8 predose and at 0.5, 1, 2, 4, 6, 8, 12, and 24 hrs postdose, with sparse sampling thereafter. Matched cytokine BMx samples were collected. The PK analysis population comprised pts with at least one measurable EIK1001 concentration (1563 observations from 94 pts). PK data were analyzed using non-linear mixed effects in Phoenix (v8.3). Covariate effects of the combination drugs were tested using a stepwise approach with a significance level of 0.05 for forward addition. All other covariates were evaluated using exploratory plots and formally tested using a full matrix approach. Empirical Bayes estimates were used to generate individual steady-state concentration-time profiles and calculate post-hoc PK parameters. Exploratory analyses of exposure-safety and exposure-efficacy were conducted. Results: EIK1001 PK was linear and dose-proportional over the doses studied. Tmax ranged from 4-12 hrs with no accumulation. Pop-PK analysis indicated that body size influenced clearance, but intrinsic factors of age, gender, tumor type, ECOG status, or hepatic/renal impairment (mild/moderate) did not. Combination drugs did not influence clearance. These attributes support BSA-based dosing and inform inclusion/exclusion criteria for future studies. On C1D1, time-dependent increases in IL-6, IL-8, IFNγ, and IP-10 returned to baseline within 24 hrs. An earlier IL-8 increase (Tmax 3-5 hr) is consistent with TLR8 activation on various cells including neutrophils, whereas the delayed increase of IFNγ/IP-10 (Tmax 5-8 hr) suggests a downstream effect. Dose-dependent increases in cytokines were observed, with median peak changes from baseline of 1.13- to 7.97-fold for IFNγ and 0.63- to 12.1-fold for IP-10. The 2 highest doses provided evidence of robust target engagement alone or in combination. Conclusion: The linear, dose-proportional PK of EIK1001 is well described by the Pop-PK model. Increases in IFNγ and IP-10 were consistent with the anticipated mechanism of action, with doses representing target engagement identified. Further development of EIK1001 is underway. Citation Format: Drew Rasco, Manish Patel, Melissa Johnson, Anthony Tolcher, David Sommerhalder, Omid Hamid, Angela Alistar, Jarema Kochan, Etah Kurland, Meihua Wang, Carolyn Cho, Sam Rebello. Pharmacokinetic/biomarker (PK/BMx) analysis of the toll-like receptor 7 and 8 (TLR7/8) agonist EIK1001 in phase 1 studies in participants (Pts) with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7172.

Nlmixr2 Versus NONMEM: An Evaluation of Maximum A Posteriori Bayesian Estimates Following External Evaluation of Gentamicin and Tobramycin Population Pharmacokinetic Models.

The objective of this project is to compare the results of the same study carried out on NONMEM and nlmixr2. This analysis consists of evaluating previously published population pharmacokinetic models of gentamicin and tobramycin in our population of interest with sparse concentrations. A literature review was performed to determine the gentamicin and tobramycin models in critically ill adult patients. In parallel, gentamicin and tobramycin dosing data, information on the treatment, the patient, and the bacteria were collected retrospectively in 2 Quebec establishments. The external evaluations were previously performed using NONMEM Version 7.5. Model equations were rewritten with R, and external evaluations were performed using nlmixr2. Predictive performance was assessed based on the estimation of bias and imprecision of the prediction error for maximum a posteriori (MAP) Bayesian PK parameter and observed concentrations. Comparison between nlmixr2 and NONMEM was performed on 4 gentamicin and 3 tobramycin population pharmacokinetic models. Compared to NONMEM, for gentamicin and tobramycin clearance and central volume of distribution, nlmixr2 produced individual pharmacokinetic parameters with bias values ranging from -32.5% to 5.67% and imprecision values ranging from 6.33% to 32.5%. Despite these differences, population bias and imprecision for sparse concentrations were low and ranged from 0% to 5.3% and 0.2% to 6.5%, respectively. The external evaluations performed with both software packages resulted in the same interpretation in terms of population predictive performance for all 7 models. Nlmxir2 showed comparable predictive performance with NONMEM with sparse concentrations that are, at most, sampled twice within a single dose administration (peak and trough).

In vitro PK/PD modeling of tyrosine kinase inhibitors in non-small cell lung cancer cell lines.

Tyrosine kinase inhibitors (TKIs) are routinely prescribed for the treatment of non-small cell lung cancer (NSCLC). As with all medications, patients can experience adverse events due to TKIs. Unfortunately, the relationship between many TKIs and the occurrence of certain adverse events remains unclear. There are limited invivo studies which focus on TKIs and their effects on different regulation pathways. Many invitro studies, however, that investigate the effects of TKIs observe additional changes, such as changes in gene activations or protein expressions. These studies could potentially help to gain greater understanding of the mechanisms for TKI induced adverse events. However, in order to utilize these pathways in a pharmacokinetic/pharmacodynamic (PK/PD) framework, an invitro PK/PD model needs to be developed, in order to characterize the effects of TKIs in NSCLC cell lines. Through the use of ordinary differential equations, cell viability data and nonlinear mixed effects modeling, an invitro TKI PK/PD model was developed with estimated PK and PD parameter values for the TKIs alectinib, crizotinib, erlotinib, and gefitinib. The relative standard errors for the population parameters are all less than 25%. The inclusion of random effects enabled the model to predict individual parameter values which provided a closer fit to the observed response. It is hoped that this model can be extended to include invitro data of certain pathways that may potentially be linked with adverse events and provide a better understanding of TKI-induced adverse events.

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B

BackgroundPharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy. ObjectivesThis study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B. MethodsIn this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance. ResultsWe included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction. ConclusionPK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible.

Specific Targeting of Zinc Transporter LIV-1 with Immunocytokine Containing Anti-LIV-1 VHH and Human IL-2 and Evaluation of its In vitro Antitumor Activity.

Interleukin 2 (IL-2) is a vital cytokine in the induction of T and NK cell responses, the proliferation of CD8+ T cells, and the effective treatment of human cancers such as melanoma and renal cell carcinoma. However, widespread use of this cytokine is limited due to its short half-life, severe toxicity, lack of specific tumor targeting, and activation of Treg cells mediated by high-affinity interleukin-2 receptors. In this study, a tumor-targeting LIV-1 VHH-mutIL2 immunocytokine with reduced CD25 (α chain of the high-affinity IL-2 receptor) binding activity was developed to improve IL-2 half-life by decreasing its renal infiltration in comparison with wild and mutant IL-2 molecules. The recombinant immunocytokine was designed and expressed. The biological activity of the purified fusion protein was investigated in in vitro and in vivo experiments. The fusion protein represented specific binding to MCF7 (the breast cancer cell line) and more efficient cytotoxicity than wild-type IL-2 and mutant IL-2. The PK parameters of the recombinant immunocytokine were also improved in comparison to the IL-2 molecules. The observed results showed that LIV1-mIL2 immunocytokine could be considered as an effective agent in the LIV-1-targeted treatment of cancers due to its longer half-life and stronger cytotoxicity.

A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics.

Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic's physicochemical parameters and its corresponding ADME properties. The model's compound-specific input includes molecular weight, molecular size (Stoke's radius), molecular charge, binding affinity to FcRn, and specific antigen affinity. Through derived and fitted empirical relationships, the model demonstrates the effect of these compound-specific properties on antibody disposition in both plasma and peripheral tissues using observed PK data in mice and humans. The mPBPK model applies the two-pore hypothesis to predict size-based clearance and exposure of full-length antibodies (150kDa) and antibody fragments (50-100kDa) within a onefold error. We quantitatively relate antibody charge and PK parameters like uptake rate, non-specific binding affinity, and volume of distribution to capture the relatively faster clearance of positively charged mAb as compared to negatively charged mAb. The model predicts the terminal plasma clearance of slightly positively and negatively charged antibody in humans within a onefold error. The mPBPK model presented in this work can be used to predict the target-mediated disposition of a drug when compound-specific and target-specific properties are known. To our knowledge, a combined effect of antibody weight, size, charge, FcRn, and antigen has not been incorporated and studied in a single mPBPK model previously. By conclusively incorporating and relating a multitude of protein's physicochemical properties to observed PK, our mPBPK model aims to contribute as a platform approach in the early stages of drug development where many of these properties can be optimized to improve a molecule's PK and ultimately its efficacy.

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia.

Nadolol is a long-acting non-selective β-adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (Rpre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration-time curve (AUC0-t), the maximum concentration in plasma (Cmax), and CL (clearance). The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the Rpre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia.

Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation-A Step toward Correct Dosing.

During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial drugs are frequently used, and appropriate dosing is challenging due to there being limited data to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following 600 mg intravenous (IV) injections every 8 h, and these were used to develop a population pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling approach. Monte Carlo simulation generated 5000 patients' individual PK parameters and corresponding concentration-time profiles using the PopPK model, following the administration of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios. Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently, monitoring is essential.

Safety, Tolerability, and Pharmacokinetics of Voriconazole for Injection in Two Preparations in Chinese Healthy Adult Volunteers.

Voriconazole is a second-generation, synthetic, triazole antifungal drug based on the structure of fluconazole. We compared the safety, tolerability, and pharmacokinetic characteristics of voriconazole for injection (200mg) manufactured by at a dose of 6mg/kg in Chinese healthy adult volunteers. This was a single-center, randomized, open, 2-preparation, single-dose, 2-period, 2-sequence, crossover bioequivalence clinical trial. Twenty-four eligible, healthy, male, and female volunteers were assigned randomly to one of 2 dose-sequence groups (test-reference group or reference-test group) in a 1:1 block. The voriconazole concentration in plasma was determined by protein precipitation and high-performance liquid chromatography-tandem mass spectrometry. The main PK parameters were calculated on the basis of a noncompartmental model. The ratio of the geometric mean of the maximum plasma drug concentration, area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity of the test preparation, and the reference preparation was 100.4%, 102%, and 102.2%, respectively. The 90% confidence intervals were between 80% and 125%, indicating that the 2 preparations were bioequivalent. The adverse events experienced by healthy adult volunteers were mild. Both preparations had a good safety profile.