Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.

ABSTRACT: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.

Inter-regional pharmacokinetics and exposure-response analyses of belimumab in patients with system lupus erythematosus.

AIMS: The pharmacokinetics (PK) of belimumab, a human immunoglobulin G1λ (IgG1λ) monoclonal antibody treatment for systemic lupus erythematosus (SLE), have been well reported. Clinical PK data in healthy participants and patients with SLE from Mainland China suggest lower-than-expected belimumab exposure. This study assessed inter-regional differences in belimumab exposure and efficacy via the exposure-response relationship to inform any dose-adjustment requirements. METHODS: Data from nine interventional belimumab studies in healthy participants and patients with SLE were used to update two-compartment PK models with first-order subcutaneous (SC) absorption, and a logistic regression model characterizing the 52-week SLE Responder Index (SRI) response in adult and paediatric patients with SLE. Covariates of belimumab PK and efficacy were identified using forward selection (P > .05) and backward elimination (P < .01). The models were evaluated using statistical tests and visual predictive checks. RESULTS: Baseline fat-free mass was the most significant covariate affecting belimumab PK; baseline albumin and IgG concentrations were also PK covariates. After adjusting for covariates, Mainland Chinese patients had significantly higher observed belimumab clearance (28%) and central volume of distribution (20%) than other populations, leading to lower-than-expected exposures. Despite this, following the same dose, they were expected to have almost identical SRI response rates vs. other populations from the exposure-response analysis. CONCLUSIONS: Belimumab 10 mg kg-1 intravenously every 4 weeks, or 200 mg SC every week, would achieve the maximum treatment effect for North East Asian patients with SLE (including Mainland Chinese) and similar responses to patients from other regions, despite lower reported exposures in Chinese patients.

Teleneurocritical Care for Patients with Large Vessel Occlusive Ischemic Stroke Treated by Thrombectomy.

BACKGROUND: Teleneurocritical care (TNCC) provides 24/7 virtual treatment of patients with neurological disease in the emergency department or intensive care unit. However, it is not known if TNCC is safe, effective, or associated with similar outcomes compared with in-person neurocritical care. We aim to determine the effect of daily inpatient consults from TNCC on the outcomes of patients with large vessel occlusive acute ischemic stroke treated by thrombectomy. METHODS: A multicenter, retrospective cohort of consecutive patients ≥ 18 years old with acute ischemic stroke from a large vessel occlusion treated by thrombectomy were identified from 2018 to 2021 within a telehealth network of an integrated not-for-profit health care system in the United States. The primary end point was good functional outcome, i.e., modified Rankin Scale 0-3, at the time of hospital discharge in patients receiving in-person neurocritical care versus TNCC. RESULTS: A total of 437 patients met inclusion criteria, 226 at the in-person hospital (median age 67, 53% women) and 211 at the two TNCC hospitals (median age 74, 49% women). The rate of successful endovascular therapy (modified Thrombolysis in Cerebral Infarction score 2b-3) was not different among hospitals. Good functional outcome at discharge was similar between in-person neurocritical care and TNCC (in-person 31.4% vs. TNCC 33.5%, odds ratio 0.88, 95% confidence interval 0.6-1.3; p = 0.64). Only National Institutes of Health stroke scale and age were multivariable predictors of outcome. There were no differences in mortality (9.3% vs. 13.2%, p = 0.19), intensive care unit length of stay (2.1 vs. 1.9 days, p = 0.39), or rate of symptomatic intracerebral hemorrhage (6.8% vs. 6.6%, p = 0.47) between in-person neurocritical care and TNCC. CONCLUSIONS: Teleneurocritical care allows for equivalent favorable functional outcomes compared with in-person neurocritical care for patients with acute large vessel ischemic stroke receiving thrombectomy. The standardized protocols used by TNCC in this study, specifically the comprehensive 24/7 treatment of patients in the intensive care unit for the length of their stay, may be relevant for other health systems with limited in-person resources; however, additional study is required.

Splicing Modulation Results in Aberrant Isoforms and Protein Products of p53 Pathway Genes and the Sensitization of B Cells to Non-Genotoxic MDM2 Inhibition.

Several molecular subtypes of cancer are highly dependent on splicing for cell survival. There is a general interest in the therapeutic targeting of splicing by small molecules. E7107, a first-in-class spliceosome inhibitor, showed strong growth inhibitory activities against a large variety of human cancer xenografts. Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous hematologic malignancy, with approximately 90% of cases being TP53 wild-type at diagnosis. An increasing number of studies are evaluating alternative targeted agents in CLL, including MDM2-p53 binding antagonists. In this study, we report the effect of splicing modulation on key proteins in the p53 signalling pathway, an important cell death pathway in B cells. Splicing modulation by E7107 treatment reduced full-length MDM2 production due to exon skipping, generating a consequent reciprocal p53 increase in TP53WT cells. It was especially noteworthy that a novel p21WAF1 isoform with compromised cyclin-dependent kinase inhibitory activity was produced due to intron retention. E7107 synergized with the MDM2 inhibitor RG7388, via dual MDM2 inhibition; by E7107 at the transcript level and by RG7388 at the protein level, producing greater p53 stabilisation and apoptosis. This study provides evidence for a synergistic MDM2 and spliceosome inhibitor combination as a novel approach to treat CLL and potentially other haematological malignancies.

SF3B1 Mutations Are Associated with Resistance to Non-Genotoxic MDM2 Inhibition in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a genetically and clinically heterogeneous malignancy affecting older individuals. There are a number of current treatment options for CLL, including monoclonal antibodies, targeted drugs, chemotherapy, and different combinations of these. However, for those patients who are intrinsically treatment resistant, or relapse following initial responses, novel targeted therapies are still needed. Targeting the mouse double-minute-2 human homolog (MDM2), a primary negative regulator of p53, is an appealing therapeutic strategy for non-genotoxic reactivation of p53, since the TP53 gene is in its wild-type state at diagnosis in approximately 90% of patients. Mutated SF3B1 and TP53 are both associated with more aggressive disease, resistance to therapies and poorer overall survival for CLL. In this study, we performed a screen for SF3B1 and TP53 mutations and tested RG7388 (idasanutlin), a second-generation MDM2 inhibitor, in a cohort of CLL primary patient samples. SF3B1 mutations were detected in 24 of 195 cases (12.3%) and found associated with poor overall survival (hazard ratio [HR] 2.12, p = 0.032) and high CD38 expression (median CD38 (%) 32 vs. 5; p = 0.0087). The novel striking finding of this study was an independent link between SF3B1 mutational status and poor response to RG7388. Overall, SF3B1 mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors.

The safety and clinical effectiveness of rapid infusion with CT-P10 in patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia: A retrospective non-interventional post-authorization safety study in Europe.

Rapid infusion (RI) of the rituximab biosimilar CT-P10 is currently only an approved treatment regimen for the treatment of rheumatoid arthritis. Although both CT-P10 and reference rituximab are known to be frequently administered using a RI regimen (≤90 min) in clinical practice, published data on the safety of RI of CT-P10 in patients with NHL and CLL are limited. Hence, this study collected real-world safety and effectiveness data on RI-CT-P10 from the medical records of 196 patients with NHL or CLL in 10 European centers, 6 months after the date of the first RI (index date); the infusion-related reaction (IRR) rate was compared to previously published data. Ten percent (95% confidence interval 6%-15%; n = 20/196) of patients experienced an infusion-related reaction (IRR) on day 1-2 post-index, which was not significantly different (p = 0.45) to the IRR rate for rituximab described in a previous meta-analysis (8.8%). During the observation period, 2% of patients experienced grade 3-5 IRRs and 85% (n = 166) experienced an adverse event (non-IRR). The most common reason for discontinuation of first-line CT-P10 was planned treatment completion (81%; n = 158). Complete response and partial response to CT-P10 was observed in 74% (n = 142/192) and 22% (n = 42/192) of patients, respectively. The results of this real-world study demonstrate that the safety and effectiveness profile of RI-CT-P10 is similar to RI of reference rituximab and therefore support the current use of RI-CT-P10 in patients with NHL and CLL.

Population pharmacokinetics of tanezumab following intravenous or subcutaneous administration to patients with osteoarthritis or chronic low back pain.

AIMS: Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. METHODS: Data from 10 studies of IV or SC tanezumab (2.5-20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2-compartment model with linear and nonlinear elimination (based on prior analysis of pre-2015 IV osteoarthritis studies) was expanded to include other pre-2015 studies. In Step 2, post-2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment-emergent anti-drug antibodies (TE ADA). RESULTS: SC bioavailability was estimated at 62-76%. The key disposition parameters CL, Vc , Vp and KM were estimated to be 0.133 L d-1 , 2.6 L, 1.77 L and 31.2 µg L-1 , respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9-11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5-10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4-8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6-7%). CONCLUSION: Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK.

Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy. METHODS: Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro. RESULTS: We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib. CONCLUSION: Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.

Real-world tyrosine kinase inhibitor treatment pathways, monitoring patterns and responses in patients with chronic myeloid leukaemia in the United Kingdom: the UK TARGET CML study.

Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML.

DAP Kinase-Related Apoptosis-Inducing Protein Kinase 2 (DRAK2) Is a Key Regulator and Molecular Marker in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and it is characterized by a marked degree of clinical heterogeneity. An impaired balance between pro- and anti-apoptotic stimuli determines chemorefractoriness and outcome. The low proliferation rate of CLL cells indicates that one of the primary mechanisms involved in disease development may be an apoptotic failure. Here, we study the clinical and functional significance of DRAK2, a novel stress response kinase that plays a critical role in apoptosis, T-cell biology, and B-cell activation in CLL. We have analyzed CLL patient samples and showed that low expression levels of DRAK2 were significantly associated with unfavorable outcome in our CLL cohort. DRAK2 expression levels showed a positive correlation with the expression of DAPK1, and TGFBR1. Consistent with clinical data, the downregulation of DRAK2 in MEC-1 CLL cells strongly increased cell viability and proliferation. Further, our transcriptome data from MEC-1 cells highlighted MAPK, NF-κB, and Akt and as critical signaling hubs upon DRAK2 knockdown. Taken together, our results indicate DRAK2 as a novel marker of CLL survival that plays key regulatory roles in CLL prognosis.

Non-genotoxic MDM2 inhibition selectively induces a pro-apoptotic p53 gene signature in chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous hematologic malignancy. In approximately 90% of cases the TP53 gene is in its wildtype state at diagnosis of this malignancy. As mouse double-minute-2 homolog (MDM2) is a primary repressor of p53, targeting this protein is an attractive therapeutic approach for non-genotoxic reactivation of p53. Since the discovery of the first MDM2 inhibitor, Nutlin-3a, newer potent and bioavailable compounds have been developed. In this study we tested the second-generation MDM2 inhibitor, RG7388, in patient-derived CLL cells and normal cells, examining its effect on the induction of p53-transcriptional targets. RG7388 potently decreased viability in p53-functional CLL cells, whereas p53-non-functional samples were more resistant to the drug. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic (PUMA, BAX) and extrinsic (TNFRSF10B, FAS) pathways of apoptosis, as well as MDM2 Only a slight induction of CDKN1A was observed and upregulation of pro-apoptotic genes dominated, indicating that CLL cells are primed for p53-dependent apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. Importantly, we observed a preferential pro-apoptotic signature in CLL cells but not in normal blood and bone marrow cells, including CD34+ hematopoietic cells. These data support the further evaluation of MDM2 inhibitors as a novel additional treatment option for patients with p53-functional CLL.

The effect of digital rectal exam on the 4Kscore for aggressive prostate cancer.

BACKGROUND: The 4Kscore is a new commercially available blood-based diagnostic test which predicts risk for aggressive, clinically significant prostate cancer on prostate biopsy. The 4Kscore is currently restricted to patients who have not had a digital rectal exam (DRE) in the previous 96 h, owing to prior mixed data suggesting that prostate specific antigen (PSA) isoforms may increase by a statistically significant-if not necessarily clinically significant-amount shortly after DRE. Our primary objective was to determine if 4Kscore test results are affected by a preceding DRE. METHODS: Participants at a Prostate Cancer Awareness Week screening event sponsored by the Prostate Conditions Education Council filled out clinical history questionnaires and had blood samples for 4Kscore testing drawn prior to DRE, then 15-45 min following DRE. Patients with prior cancer diagnosis, 5-alpha reductase inhibitor medication use, or lower urinary tract procedures in the prior 6 months were excluded, resulting in a population of 162 participants for analysis. Values were then compared to determine if there was a significant difference in 4Kscore following DRE. RESULTS: A statistically significant increase was seen in levels of 3 kallikreins measured (total PSA, free PSA, and intact PSA; median <0.03 ng/mL for all). This resulted in a small but statistically significant decrease in post-DRE 4Kscore (median absolute score decrease 0.43%). Using a 4Kscore cutoff of 7.5% resulted in reclassification of 10 patients (6.2%), nine of whom were "downgraded" from above the cutoff to below. CONCLUSIONS: If the blood draw for the 4 K score is performed after a screening DRE, there is a statistically significant difference in the 4 K score results, but in the vast majority of cases it would not affect clinical decision making.

Impact of non-adherence on the safety and efficacy of uric acid-lowering therapies in the treatment of gout.

AIMS: Dual-urate-lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs. METHODS: The impact of poor medication adherence was studied using two-compartment pharmacokinetic (PK) models based on published evidence, and a semi-mechanistic four-compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual-ULT in gout patients with either under-excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random. RESULTS: Simulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under-excreters taking a 20-day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria. CONCLUSIONS: Suboptimal medication adherence may compromise the safety and efficacy of mono- and dual-ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate.

Impact of Non-Adherence and Flare Resolution on the Cost-Effectiveness of Treatments for Gout: Application of a Linked Pharmacometric/Pharmacoeconomic Model.

BACKGROUND: Dual urate-lowering therapy (ULT) with lesinurad in combination with either allopurinol or febuxostat is an option for patients with gout unsuccessfully treated on either monotherapy. Treatment failure is often a result of poor medication adherence. Imperfect adherence in clinical trials may lead to biased estimates of treatment effect and confound the results of cost-effectiveness analyses. OBJECTIVES: To estimate the impact of varying medication adherence on the cost effectiveness of lesinurad dual therapy and estimate the value-based price of lesinurad at which the incremental cost-effectiveness ratio is equal to £20,000 per quality-adjusted life-year (QALY). METHODS: Treatment effect was simulated using published pharmacokinetic-pharmacodynamic models and scenarios representing adherence in clinical trials, routine practice, and perfect use. The subsequent cost and health impacts, over the lifetime of a patient cohort, were estimated using a bespoke pharmacoeconomic model. RESULTS: The base-case incremental cost-effectiveness ratios comparing lesinurad dual ULT with monotherapy ranged from £39,184 to £78,350/QALY gained using allopurinol and £31,901 to £124,212/QALY gained using febuxostat, depending on the assumed medication adherence. Results assuming perfect medication adherence imply a per-quarter value-based price of lesinurad of £45.14 when used in dual ULT compared with allopurinol alone and £57.75 compared with febuxostat alone, falling to £25.41 and £3.49, respectively, in simulations of worsening medication adherence. CONCLUSIONS: The estimated value-based prices of lesinurad only exceeded that which has been proposed in the United Kingdom when assuming both perfect drug adherence and the eradication of gout flares in sustained treatment responders.

How much is enough? Using Delphi to explore the clinical-contact-time and return-to-practice needs of military nurses.

Aim Military nurses are required to deploy worldwide at any time to support British forces. They must maintain military and clinical skills, and fulfil other military commitments as required. These diverse responsibilities make it challenging for military nurses to maintain the level of clinical expertise they require for short-notice deployments. A service evaluation was conducted to investigate issues related to clinical contact time (CCT) and to return to practice (RTP) for military nurses. Method A consultative approach was taken in the form of a modified Delphi study, followed by a military judgement panel (focus group). Results Two aspects of the study are reported here: CCT and RTP. Panellists considered that policy rather than guidance is needed to ensure military nurses achieve the requisite CCT to prepare them for operational deployment. Additionally, there was a broad consensus on a range of issues, including minimum CCT for specific groups and mechanisms to support those returning to practice. Conclusion Maintaining clinical skills, and the challenges of returning to practice, require careful consideration in a mobile workforce with wide-ranging commitments. Prescribing CCT, ensuring assignment orders specify CCT and the introduction of job plans should help military nurses maintain their core and specialist nursing skills, guide commanders and reinforce the culture of 'hands-on nursing' as a valid use of time.

Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain.

AIMS: The aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight. METHODS: Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme-linked immunosorbent assay. RESULTS: A two compartment model with parallel linear and non-linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1 ), peripheral volume (V2 ), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 l day(-1) , 2.71 l, 1.98 l, 0.371 l day(-1) , 8.03 µg day(-1) and 27.7 ng ml(-1) , respectively. Inter-individual variability (IIV) was included on CL, V1 , V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV. CONCLUSIONS: The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.

Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers.

PURPOSE: To quantify pharmacokinetic (PK) and pharmacodynamic (PD) relationships of various classes of GABAA agonists in healthy volunteers, in order to investigate the sensitivity of the biomarker responses due to differing GABAA-subtype selectivity and to explore the correlation between biomarker responses and side effects of these drugs. METHODS: A comprehensive search was conducted for published placebo-controlled clinical studies of non- and α1-selective GABAA drugs in healthy volunteers. PK/PD models were developed for concentrations and biomarker outcomes (saccadic eye movement (SEM), visual analogue scale (VAS), digit symbol substitution task (DSST), and critical flicker fusion test (CFFT)) extracted from included studies. Predicted responses and equivalent doses for biomarkers (based on predicted response) were used to compare drug effects. And the relationship between biomarkers and safety was explored by linear regression. RESULTS: A total of 2237 data from 163 articles were included. Based on PK and placebo effect modeling, linear biomarker-concentration relationships well fit the data. The α1-selective compounds had similar equivalent doses for VAS, DSST, and CFFT (4.7-6.7 mg), which were about three to seven times lower than that for SEM (14.4-35.5 mg), while such difference was less evident for non-selective drugs. DSST had the highest correlations with incidences of somnolence and dizziness. CONCLUSIONS: The integral PK/PD models of GABAA agonists were established in healthy volunteers. SEM was identified as the most sensitive biomarker in differentiating GABAA receptor α1 subtype selective compounds. The exploratory analysis implied that different relationships existed between the drug effects on biomarkers and the adverse event profiles in healthy volunteers.