Acellular Fish Skin Grafts for Treatment of Periocular Skin Defects.

PURPOSE: To describe the outcomes of acellular fish skin grafts for repair of periocular anterior lamella skin defects after Mohs surgery for skin cancers. METHODS: Following the institutional review board approval, we conducted a retrospective chart review of patients treated with acellular fish skin grafts between January 2022 and December 2023. Indication was to repair defects after Mohs excision of basal cell carcinoma and squamous cell carcinoma. Demographics, smoking and diabetes status, diagnosis, defect location, graft size, and complications were evaluated. Outcomes were analyzed using the scar cosmesis assessment and rating scale. RESULTS: Six patients (3 females and 3 males) with a mean age of 60.8 (range 44-80) had Mohs surgery for basal cell carcinoma (4) and squamous cell carcinoma (2). Location of defects included eyebrow (3 cases), lateral nasal wall (1 case), lower eyelid (1 case), and medial lower eyelid/nasal wall (1 case). Defect size ranged from 8 × 10 mm to 30 × 40 mm. Two patients had more than 1 application of xenograft. One patient developed a mild cicatricial ectropion. No other postoperative complications were seen, and all had good wound healing and cosmetically acceptable results. CONCLUSIONS: In this pilot study, acellular fish skin xenografts are shown to be promising skin graft substitutes in patients with Mohs defects and decrease the need for autologous skin harvesting or allogenic skin donation.

Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta-Analysis.

B-cell maturation antigen (BCMA)-targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T-cell activation and cytokine elevations leading to cytokine release syndrome (CRS) in some patients, which can be potentially life-threatening. However, systematic evaluation of the risk of CRS with BCMA-targeting BsAb and CAR-T therapies, and comparisons across different routes of BsAb administration (intravenous (i.v.) vs. subcutaneous (s.c.)) have not previously been conducted. This study utilized a meta-analysis approach to compare the CRS profile in BCMA-targeting CAR-T vs. BsAb immunotherapies administered either i.v. or s.c. in patients with RRMM. A total of 36 studies including 1,560 patients with RRMM treated with BCMA-targeting CAR-T and BsAb therapies were included in the analysis. The current analysis suggests that compared with BsAbs, CAR-T therapies were associated with higher CRS incidences (88% vs. 59%), higher rates of grade ≥ 3 CRS (7% vs. 2%), longer CRS duration (5 vs. 2 days), and more prevalent tocilizumab use (44% vs. 25%). The proportion of CRS grade ≥ 3 may also be lower (0% vs. 4%) for BsAb therapies administered via the s.c. (3 studies, n = 311) vs. i.v. (5 studies, n = 338) route. This meta-analysis suggests that different types of BCMA-targeting immunotherapies and administration routes could result in a range of CRS incidence and severity that should be considered while evaluating the benefit-risk profiles of these therapies.

Optimizing Ophthalmology Patient Education via ChatBot-Generated Materials: Readability Analysis of AI-Generated Patient Education Materials and The American Society of Ophthalmic Plastic and Reconstructive Surgery Patient Brochures.

PURPOSE: This study aims to compare the readability of patient education materials (PEM) of the American Society of Ophthalmic Plastic and Reconstructive Surgery to that of PEMs generated by the AI-chat bots ChatGPT and Google Bard. METHODS: PEMs on 16 common American Society of Ophthalmic Plastic and Reconstructive Surgery topics were generated by 2 AI models, ChatGPT 4.0 and Google Bard, with and without a 6th-grade reading level prompt modifier. The PEMs were analyzed using 7 readability metrics: Flesch Reading Ease Score, Gunning Fog Index, Flesch-Kincaid Grade Level, Coleman-Liau Index, Simple Measure of Gobbledygook Index Score, Automated Readability Index, and Linsear Write Readability Score. Each AI-generated PEM was compared with the equivalent American Society of Ophthalmic Plastic and Reconstructive Surgery PEM. RESULTS: Across all readability indices, PEM generated by ChatGPT 4.0 consistently had the highest readability scores, indicating that the material generated by this AI chatbot may be most difficult to read in its unprompted form (Flesch Reading Ease Score: 36.5; Simple Measure of Gobbledygook: 14.7). Google's Bard was able to generate content that was easier to read than both the American Society of Ophthalmic Plastic and Reconstructive Surgery and ChatGPT 4.0 (Flesch Reading Ease Score: 52.3; Simple Measure of Gobbledygook: 12.7). When prompted to produce PEM at a 6th-grade reading level, both ChatGPT 4.0 and Bard were able to significantly improve in their readability scores, with prompted ChatGPT 4.0 being able to consistently generate content that was easier to read (Flesch Reading Ease Score: 67.9, Simple Measure of Gobbledygook: 10.2). CONCLUSION: This study suggests that AI tools, when guided by appropriate prompts, can generate accessible and comprehensible PEMs in the field of ophthalmic plastic and reconstructive surgeries, balancing readability with the complexity of the necessary information.

Case-control matching-guided exposure-efficacy relationship for avelumab in patients with urothelial carcinoma.

Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case-control matching to account for this bias and better understand the E-R relationship for avelumab in urothelial carcinoma, a PD-L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN-100 was utilized which is a phase III study of avelumab in first-line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best-supportive care leading to approval in the United States, Europe, and other countries. A post hoc case-control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.

Optimizing benefit/risk in oncology: Review of post-marketing dose optimization and reflections on the road ahead.

Oncology therapies shifted from chemotherapy to molecularly targeted agents and finally to the era of immune-oncology agents. In contrast to cytotoxic agents, molecularly targeted agents are more selective, exhibit a wider therapeutic window, and may maximally modulate tumor growth at doses lower than the maximum tolerated dose (MTD). However, first-in-patient oncology studies for molecularly targeted agents continued to evaluate escalating doses using limited number of patients per dose cohort assessing dose-limiting toxicities to identify the MTD which is commonly selected for further development adopting a 'more is better' approach that led to several post-marketing requirement (PMR) studies to evaluate alternative, typically lower, doses or dosing frequencies to optimize the benefit-risk profile. In this review, post-marketing dose optimization efforts were reviewed including those required by a regulatory pathway or voluntarily conducted by the sponsor to improve efficacy, safety, or method of administration. Lessons learned and future implications from this deep dive review are discussed considering the evolving regulatory landscape on dose optimization for oncology compounds.

Intravascular Large B-cell Lymphoma Diagnosed by Nasal Biopsy in a Patient Presenting with Bilateral Ptosis and Ophthalmoplegia.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of lymphoma, involving the lumen of predominantly small blood vessels, especially capillaries. The orbit is an uncommon site of involvement for IVLBCL, and diagnosis before autopsy is even more rare as most cases are established post-mortem. Herein, the authors describe a 73-year-old male who presented with 3 weeks of progressive bilateral ptosis and ophthalmoplegia. Computed tomography (CT) and subsequent magnetic resonance imaging (MRI) revealed diffuse abnormal thickening and enhancement of bilateral orbital apices, superior orbital fissures, and cavernous sinus, along with persistent focal opacification of the left frontal and ethmoid sinuses. Infectious and inflammatory workup of serum and cerebrospinal fluid was negative. Ethmoidal sinus and middle turbinate biopsy confirmed intravascular large B-cell lymphoma and the patient was started on R-CHOP chemotherapy regimen.

Comparison of Postoperative Infection Rates After Office-based Oculoplastic Procedures Using Sterile and Clean Gloves.

PURPOSE: To compare postoperative infection (PI) rates using sterile and clean-boxed gloves in office-based oculoplastic procedures. METHODS: Prospective, comparative study of patients undergoing oculoplastic procedures by a single surgeon (RS) in an office-based procedure room between October 2018 and September 2020. Participants included were 18 years or older. Excluded were patients on oral antibiotics within 2 weeks before the procedure, had a follow-up period of less than 1 week, had a contaminated wound, had complex reconstructions, or had multiple simultaneous procedures performed. Oculoplastic procedures were performed using either sterile or clean-boxed gloves. The main outcome measure was the frequency of postoperative infection. RESULTS: Three thousand one hundred twenty-nine patients, 1,815 (58%) of whom were women, with a mean age of 60 (18-102) years were included. One thousand five hundred seventy procedures were performed with sterile gloves, while 1,559 were performed with clean-boxed gloves. The patients in the 2 groups were similar in age, gender, and number of high-risk individuals. One patient in the sterile glove group who underwent upper blepharoplasty (0.064%) and one patient (0.064%) in the clean-boxed glove group who had an external levator advancement blepharoptosis repair developed PI. Neither patient had risk factors for infection, and both infections resolved after 1 week of oral amoxicillin-clavulanate 875/125 mg twice daily. CONCLUSIONS: In minimally complex in-office oculoplastic procedures, using sterile versus clean-boxed gloves resulted in similar low infection rates in this large cohort. The healthcare benefits may not outweigh the costs of using sterile gloves universally for office-based oculoplastic procedures.

Tarsal Ectropion Repair With Modified Bick Eyelid Tightening and Inverting Sutures.

PURPOSE: The authors report on a 10-year experience of correcting tarsal ectropion using a combined method of modified Bick eyelid tightening (MBLT) and inverting sutures. METHODS: Retrospective, interventional case series of consecutive patients with tarsal ectropion who underwent MBLT and inverting sutures by a single surgeon (RS) between July 2010 and July 2020. Thirty-four patients, 24 of whom were female, with a mean age of 81.6 years (range 59-92) were included. Eight patients had bilateral disease. All procedures were performed under local anesthesia in an office setting. Treatment success was defined by eyelid position, symptoms, and need for reoperation. RESULTS: Thirty-one patients (91%) had a successful outcome. Three patients (9%) had satisfactory results with improved symptoms and mild residual ectropion, for which further surgery was not required. No patients had poor results. The mean follow-up time was 4.5 months (range 3-11 months). The inverting sutures were well tolerated in all cases and none had to be removed due to ocular surface discomfort. There were no visible scars from the inverting sutures in any patient at postoperative month 3. CONCLUSIONS: A combination of eyelid tightening using MBLT and inverting sutures is a simple and effective treatment for lower eyelid tarsal ectropion with minimal tissue dissection.

Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment.

AIM: This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function. METHODS: Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients. RESULTS: Thirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug. CONCLUSIONS: Hepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.

Bilateral Concurrent Endocrine Mucin-Producing Sweat Gland Carcinoma and Mucinous Carcinoma of the Eyelids.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is thought to be a precursor to mucinous carcinoma, both of which are rare. In this case report, the authors present a 55-year-old woman with concurrent EMPSGC and mucinous carcinoma manifesting with 2 distinct lesions on her left upper and lower eyelid and 1 lesion on her right lower eyelid. Biopsy and immunohistochemical staining supported primary cutaneous origin of the tumors. Systemic metastatic workup was initiated and thus far negative. The patient underwent staged slow Mohs micrographic surgery to remove one tumor at a time, with delayed reconstruction. This is the first reported case of EMPSGC and mucinous carcinoma presenting as distinct lesions both bilaterally and synchronously.

Analysis of US Food and Drug Administration Oncology Approvals on the Characterization of Hepatic Impairment Effect and Dosing Recommendations.

Patients with cancer and advanced hepatic impairment (HI) (i.e., moderate and severe impairment) are often excluded from first-in-patient, phase II, and phase III studies. Thus, dose recommendations for this subgroup of patients are often derived using a combination of dedicated phase I studies conducted in participants without cancer and a population pharmacokinetic (PK) modeling approach. A standardized risk-based approach to guide the evaluation of HI in patients with cancer is needed. In this review, we evaluated available oncology drug approvals by the US Food and Drug Administration (FDA) from 1999 to 2019, identified strategies utilized by sponsors to characterize the effect of HI on the PK of oncology drugs, and assessed regulatory expectations for each strategy. Finally, we constructed a decision tree that complements current FDA guidance to enable efficient evaluation of the effect of HI on PK and provide guidance for dose recommendations.

Real-World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men.

This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib was evaluated using three independent data sources: real-world data from pharmacy and medical claims, a de-identified real-world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1,139 men with MBC were identified; in the first-line setting, median duration of treatment was longer with palbociclib plus ET (n = 37, 8.5 months, 95% confidence interval (CI), 4.4-13.0) than ET alone (n = 214, 4.3 months, 95% CI, 3.0-5.7) and specifically, was longer with palbociclib plus letrozole (n = 26, 9.4 months, 95% CI, 4.4-14.0) than letrozole alone (n = 63, 3.0 months, 95% CI, 1.8-4.8). In the EHR-derived database, 59 men received treatment for MBC; real-world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group vs. 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib-treated men. Real-world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real-world data, and a well-established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.

Pharmacodynamic Modeling of CDK4/6 Inhibition-Related Biomarkers and the Characterization of the Relationship Between Biomarker Response and Progression-Free Survival in Patients With Advanced Breast Cancer.

Identification of a pharmacodynamic (PD) biomarker, which is predictive of the efficacy outcome, is of ultimate interest in drug development. The objectives of the current analyses are to develop the pharmacokinetic (PK)/PD model for biomarkers (thymidine kinase 1 [TK1] in serum and phosphor-retinoblastoma protein [pRb] and Ki67 in skin tissues) related to cyclin-dependent kinase (CDK) 4/6 inhibition by palbociclib and to explore the relationship of the biomarker response with the efficacy end point (progression-free survival). The data used for analysis consisted of extensive sampling of palbociclib PK and longitudinal rich sampling for the PD biomarkers TK1, pRb, and Ki67 in 26 patients. A 2-compartment model was used to describe the PK of palbociclib. A precursor-dependent indirect response PD model was developed to describe the pRb time course, whereas a similar PD model with an additional transit compartment to model the delayed effect on Ki67 and TK1 response was used to describe the Ki67 and TK1 time course. Palbociclib effect on biomarkers was modeled as a maximum inhibition model. A Cox proportional hazard model was used to assess the relationship of progression-free survival with the biomarker response. The PK/PD models adequately described the observed PK of palbociclib and the longitudinal change of pRb, Ki67, and TK1. Palbociclib exposure significantly correlated with the reduction of all 3 biomarkers, and the estimated concentration to achieve 50% inhibition of the synthesis rate values were 45.2, 42.4, 50.2 ng/mL, respectively, for pRb, Ki67, and TK1. The exploratory biomarker-response analyses showed that a longer PFS was associated with lower baseline TK1 and simulated minimum TK1. Such results may warrant further confirmation from future large-scale study. Clinical Trial Registration: NCT02499146.

Clinical significance of spatiotemporal transcriptional bursting and control.

The rapid development of technologies provides the potential to perform real-time visualization of transcriptional bursting patterns, superenhancer formation and sensitivity to perturbation, and interactions between enhancers, promoters, and regulators during the burst. The transcriptional bursting-induced fluctuation can modify cell capacities, cell-cell communications, cell responses to microenvironmental changes, and forms of cell death. A large number of clinical and translational studies describe the existence of heterogeneity among cells, tissues, and organs but mechanism-based understanding of how and why the heterogeneity exists and how it is formed. The transcriptional bursting, fluctuation, and control determine the development of heterogeneity and optimize cell functions in the cell development and differentiation, contribute to the initiation of cell dysfunction and tumorigenesis in response to environments, and development/evolvement of hyper/hyposensitivity to drugs. Spatiotemporal monitoring of transcriptional bursting and control provides a new insight and deeper understanding of spatiotemporal molecular medicine by integrating the transcriptional positioning and function with cell phenotypes, cell-cell communication, and clinical phenomes.

Pharmacokinetics, safety, activity, and biomarker analysis of palbociclib plus letrozole as first-line treatment for ER+/HER2- advanced breast cancer in Chinese women.

PURPOSE: This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China. METHODS: Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments. RESULTS: By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUCτ was 1217 and 2501 ng∙h/mL, and t½ was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed. CONCLUSIONS: Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile. CLINICAL TRIAL REGISTRATION: NCT02499146.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors.

BACKGROUND: Pharmacokinetic (PK) studies suggest that talazoparib is primarily eliminated unchanged via renal excretion. The current study investigated how varying degrees of renal impairment may affect the PK of talazoparib, and evaluated the safety and tolerability of talazoparib, in patients with advanced solid tumors with/without renal impairment. METHODS: Patients with advanced solid tumors and normal renal function or different degrees of renal impairment measured by estimated glomerular filtration rate (eGFR: mild = 60-89, moderate = 30-59, severe = 15-29 mL/min/1.73 m2) were enrolled in this open-label, non-randomized, phase I study. Talazoparib was administered orally at 0.5 mg/day for 22 days. Primary PK parameters included the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) and maximum observed plasma concentration (Cmax) at steady state (Day 22). Safety and tolerability were also investigated. RESULTS: Thirty-four patients were enrolled. At Day 22, compared with patients with normal renal function (n = 9), patients with mild (n = 9), moderate (n = 8), or severe (n = 8) renal impairment had a 12.2%, 43.0%, and 163.3% increase in talazoparib AUC0-24, and a 11.1%, 31.6%, and 89.3% increase in talazoparib Cmax, respectively. Talazoparib was generally well tolerated, and overall there were no notable differences in the treatment-emergent adverse event profile across renal function groups. CONCLUSIONS: Exposure to talazoparib increased with worsening renal impairment. Overall, this study confirms current dosing recommendations in patients with mild and moderate renal impairment (1 mg/day and 0.75 mg/day, respectively) and indicates that a lower starting dose of 0.5 mg/day should be considered for patients with severe renal impairment. CLINICAL TRIALS REGISTRATION: NCT02997163.

Impact of Dose Reduction on Efficacy: Implications of Exposure-Response Analysis of Palbociclib.

BACKGROUND: Palbociclib is indicated for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). OBJECTIVE: Exposure-response analyses were conducted to evaluate efficacy in Asian versus non-Asian patients and in patients with versus without dose reduction in PALOMA-2. PATIENTS AND METHODS: PALOMA-2 compared palbociclib plus letrozole versus placebo plus letrozole in patients with ABC. Population pharmacokinetic analysis provided apparent palbociclib clearance (CL/F) for each patient. The time-varying exposure metric, Cavg,t, was calculated using average dose intensity and CL/F at the time of each progression-free survival (PFS) event. A Cox proportional model characterized PFS and palbociclib Cavg,t relationships. Significant prognostic factors for PFS were identified by univariate analysis, which were subsequently included in multivariate analyses, in addition to the Cavg,t effect on PFS. PFS profiles in Asian/non-Asian patients and patients with/without dose reduction were simulated and compared using observed palbociclib exposures and established exposure-response relationships. RESULTS: Patients (n = 421) received palbociclib plus letrozole (Asian = 64, non-Asian = 357; no dose reduction = 272, dose reduction = 149). Based on univariate analyses, significant prognostic factors were Ki67 score, age, and baseline aspartate aminotransferase (BAST), tumor size, alkaline phosphatase, and albumin levels. In multivariate analysis, only Ki67 and BAST remained significant. Palbociclib exposure did not significantly affect PFS in either univariate (P = 0.12) or multivariate (P = 0.44) analyses. CONCLUSIONS: This analysis suggests that palbociclib exposure has no impact on PFS when the dose reduction algorithm from palbociclib clinical trials is used. There is no difference in efficacy between Asians and non-Asians, despite the higher level of dose reductions in Asians. PFIZER: NCT01740427.

Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds.

Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions.

Palbociclib (PD-0332991) pharmacokinetics in subjects with impaired renal function.

PURPOSE: This publication describes an evaluation of the impact of different degrees of renal impairment on the pharmacokinetics and safety of palbociclib after a single 125-mg oral dose. METHODS: Thirty-one subjects were assigned to different renal function groups. Serial blood sampling for pharmacokinetics was performed up to 120 h and 168 h post-palbociclib dose for subjects with normal and impaired renal function, respectively. A separate blood sample was collected at pre-dose and 8 h after dosing to measure plasma protein binding. Plasma palbociclib was measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma protein binding samples were processed by equilibrium dialysis and measured by a validated LC-MS/MS method. RESULTS: Plasma palbociclib exposure was higher in subjects with renal impairment than in subjects with normal renal function; however, there were no marked differences in exposure across subjects with mild, moderate, and severe renal impairment. Total plasma exposure AUCinf increased by 39%, 42%, and 31% with mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. Peak exposure Cmax increased by 17%, 12%, and 15% for mild, moderate, and severe impairment, respectively. There was no obvious trend in the mean fu with worsening renal function. The PBPK model adequately described palbociclib exposure observed in subjects with moderate or severe renal impairment from this study. CONCLUSION: Palbociclib was safe and well-tolerated in a small population of subjects with normal and impaired renal function after a single oral 125 mg dose. No dose adjustment is required in patients with renal impairment.