A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

Nano optical and electrochemical sensors and biosensors for detection of narrow therapeutic index drugs.

For the first time, a comprehensive review is presented on the quantitative determination of narrow therapeutic index drugs (NTIDs) by nano optical and electrochemical sensors and biosensors. NTIDs have a narrow index between their effective doses and those at which they produce adverse toxic effects. Therefore, accurate determination of these drugs is very important for clinicians to provide a clear judgment about drug therapy for patients. Routine analytical techniques have limitations such as being expensive, laborious, and time-consuming, and need a skilled user and therefore  the nano/(bio)sensing technology leads to high interest.

Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides.

The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect.

Pharmaceutical strategies in the emerging era of antibody-based biotherapeutics for the treatment of cancers overexpressing MET receptor tyrosine kinase.

Pharmaceutical innovation in the development of novel antibody-based biotherapeutics with increased therapeutic indexes makes MET-targeted cancer therapy a clinical reality.

Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents.

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.

Crosstalk between autophagy and apoptosis: Mechanisms and therapeutic implications.

The cellular recycling process of macroautophagy, which is the mechanism by which cellular material is delivered to lysosomes via double membraned vesicles called autophagosomes, is intimately connected to programmed cell death pathways, especially apoptosis. In this article, I discuss some underlying mechanisms and their implications for improving cancer therapy and propose that the approaches that have been taken to understand the autophagy-apoptosis connection to enhance cancer drug action can serve as a model for the kinds of information that should be developed to understand how autophagy controls other biological processes as well.

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma.

Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM.

Proactive Vs Reactive Therapeutic Drug Monitoring of Infliximab in Crohn's Disease: A Cost-Effectiveness Analysis in a Simulated Cohort.

BACKGROUND: Therapeutic drug monitoring (TDM) is increasingly performed for Infliximab (IFX) in patients with Crohn's disease (CD). Reactive TDM is a cost-effective strategy to empiric IFX dose escalation. The cost-effectiveness of proactive TDM is unknown. The aim of this study is to assess the cost-effectiveness of proactive vs reactive TDM in a simulated population of CD patients on IFX. METHODS: We developed a stochastic simulation model of CD patients on IFX and evaluated the expected health costs and outcomes of a proactive TDM strategy compared with a reactive strategy. The proactive strategy measured IFX concentration and antibody status every 6 months, or at the time of a flare, and dosed IFX to a therapeutic window. The reactive strategy only did so at the time of a flare. RESULTS: The proactive strategy led to fewer flares than the reactive strategy. More patients stayed on IFX in the proactive vs reactive strategy (63.4% vs 58.8% at year 5). From a health sector perspective, a proactive strategy was marginally cost-effective compared with a reactive strategy (incremental cost-effectiveness ratio of $146,494 per quality-adjusted life year), assuming a 40% of the wholesale price of IFX. The results were most sensitive to risk of flaring with a low IFX concentration and the cost of IFX. CONCLUSIONS: Assuming 40% of the average wholesale acquisition cost of biologic therapies, proactive TDM for IFX is marginally cost-effective compared with a reactive TDM strategy. As the cost of infliximab decreases, a proactive monitoring strategy is more cost-effective.

Is Bioequivalence a Sufficient Measure of Equivalence?

This article reviews the U.S. Food and Drug Administration (FDA) regulation of generic medications-specifically, the use of bioequivalence to compare generic and brand prescriptions. New or "brand" drugs are subjected to extensive review by the FDA before they can be marketed to the public. Generics, which are posited to be identical to brands, are subject to a less extensive review process and must prove only that the generic is the "bioequivalent" (BE) of the brand drug. Generic medications are important because they comprise almost 80% of prescriptions filled in the United States and cost 80% to 85% less than brand drugs, playing a crucial role in patients' access to cost-effective treatments. However, there is dissension about whether they can be interchanged with brand drugs without any consequences for the patient, especially for Narrow Therapeutic Index (NTI) drugs, which have precise dosage requirements. The regulatory designation of bioequivalence also has implications for doctor-patient relationships, patient outcomes, and patient legal rights. This article aims to establish that there is insufficient evidence to conclude whether using bioequivalence is adequate to determine whether two drugs can be considered equivalent given the medical and legal implications that flow from deeming two drugs equivalent.

Repurposing disulfiram for treatment of Staphylococcus aureus infections.

BACKGROUND: Antimicrobial resistance is an urgent threat affecting healthcare systems worldwide. Identification of novel molecules capable of escaping current resistance mechanisms and exhibiting potent activity against highly drug-resistant strains is the unmet need of the hour. METHODS: Whole cell growth inhibition assays were used to screen and identify novel inhibitors. The hit compounds were tested against Vero cells to determine the selectivity index, followed by time-kill kinetics against Staphylococcus aureus. The ability of disulfiram to synergize with several approved drugs utilized for the treatment of S. aureus was determined using fractional inhibitory concentration indexes, followed by its ability to decimate staphyloccocal infections ex vivo. Finally, the in-vivo potential of disulfiram was determined in a neutropenic murine model of S. aureus infection. RESULTS: The screening showed that disulfiram has equipotent antibacterial activity against S. aureus, including clinical drug-resistant strains (minimum inhibitory concentration 8-16 mg/L). Disulfiram exhibited concentration-dependent bactericidal activity (∼7 log10 colony-forming units/mL reduction), synergized with linezolid and gentamycin against S. aureus, eradicated staphylococcal biofilms (64-fold better than vancomycin), decimated intracellular S. aureus better than vancomycin, exhibited longer post antibiotic effect than vancomycin, and reduced bacterial counts in murine thigh as well as vancomycin at 50 mg/kg. CONCLUSION: Taken together, disulfiram exhibits all the characteristics required for repurposing as an antibacterial targeting staphylococcal infections.

Individualized in vitro and in silico methods for predicting in vivo performance of enteric-coated tablets containing a narrow therapeutic index drug.

The efficacy of narrow therapeutic index (NTI) drugs is closely related to their plasma concentration-time profile. Particularly for these compounds interindividual variability of gastrointestinal (GI) parameters relevant to in vivo drug release may result in fluctuations of the plasma concentration. The present study focused on assessing the influence of individual GI pH- and transit profiles on drug release of enteric valproate tablet formulations by means of individualized in vitro dissolution experiments. After initial experiments simulating GI passages in average healthy adults, a novel in vitro dissolution model was used to simulate individual GI pH- and transit profiles with physiologically relevant dissolution media. Based on the dissolution profiles obtained in these experiments, individual in silico plasma profiles were generated and compared to fasted in vivo data applying a mean Euclidean distance approach. Simulated individual gastric residence time was identified as crucial parameter determining the onset of absorption, whereas the shape of the plasma profile is mainly influenced by individual valproate pharmacokinetics. The novel in vitro and in silico methods used in this study are promising tools for estimating in vivo drug release and plasma concentration in individual subjects and thus may contribute to a prospective risk assessment for NTI formulations.

A Perspective on Thiazolidinone Scaffold Development as a New Therapeutic Strategy for Toxoplasmosis.

Toxoplasma gondii is one of the most successful parasites due to its ability to infect a wide variety of warm-blooded animals. It is estimated that one-third of the world's population is latently infected. The generic therapy for toxoplasmosis has been a combination of antifolates such as pyrimethamine or trimethoprim with either sulfadiazine or antibiotics such as clindamycin with a combination with leucovorin to prevent hematologic toxicity. This therapy shows limitations such as drug intolerance, low bioavailability or drug resistance by the parasite. There is a need for the development of new molecules with the capacity to block any stage of the parasite's life cycle in humans or in a different type of hosts. Heterocyclic compounds are promissory drugs due to its reported biological activity; for this reason, thiazolidinone and its derivatives are presented as a new alternative not only for its inhibitory activity against the parasite but also for its high selectivity-level with high therapeutic index. Thiazolidinones are an important scaffold known to be associated with anticancer, antibacterial, antifungal, antiviral, antioxidant, and antidiabetic activities. The molecule possesses an imidazole ring that has been described as an antiprotozoal agent with antiparasitic properties and less toxicity. Thiazolidinone derivatives have been reportedly as building blocks in organic chemistry and as scaffolds for drug discovery. Here we present a perspective of how structural modifications of the thiazolidinone core could generate new compounds with high anti-parasitic effect and less toxic results.

Effective sustained release of 5-FU-loaded PLGA implant for improving therapeutic index of 5-FU in colon tumor.

In this study, a biodegradable implant composed of poly(lactide co-glycolide) (PLGA) and 5-fluorouracil (5-FU) was fabricated by mold method and used to impede the colon cancer via the local sustained release of 5-FU after transplanting into the peritoneal cavity. To optimize the 5-FU-implant, different factors such type of polymer, polymer-drug ratio, hydrophilic additives and organic solvents were investigated based on in vitro 5-FU release behavior. The optimized 5-FU-implant was subjected to evaluate the capacity of sustained release of 5-FU in vitro and in vivo. In addition, the pharmacokinetics and bio-distribution of 5-FU-implant were also tested in vivo after grafting into the peritoneal cavity in rat. Moreover, different doses of 5-FU-implants were compared against 5-FU injection for their antitumor activity in colon cancer model in nude mice and for their safety in health rat. The results revealed that the optimized 5-FU-implant possessed excellent sustained release of 5-FU for 2 week and no burst release were observed in vitro and in vivo. The pharmacokinetic behavior showed that higher concentration of 5-FU was found in peritoneal fluid when compared to plasma, which resulted in significantly improving antitumor activity as well as decreasing the side effect. It was proved that the 5-FU-implant was more efficacious and much safer than 5-FU bolus injection, which would be also used to overcome the reoccurrence of colon cancer after surgery.

The role of "Integrated Pulmonary Index" monitoring during morphine-based intravenous patient-controlled analgesia administration following supratentorial craniotomies: a prospective, randomized, double-blind controlled study.

OBJECTIVE: Morphine is commonly used in post-operative analgesia, but opioid-related respiratory depression causes a general reluctance for its use. The "Integrated Pulmonary Index" is a tool calculated from non-invasively obtained respiratory and hemodynamic parameters. The aim of this prospective, randomized, double blind, and placebo-controlled study is to determine a more safe and effective dose for morphine in patient-controlled analgesia following supratentorial craniotomy using the "Integrated Pulmonary Index". METHODS: This study included 60 patients (ASA I, II, and III). All patients used iv PCA for 24 h following supratentorial craniotomy. The PCA was set to administer a bolus dose of 1 mg morphine in Group 1 and 0.5 mg morphine in Group 2. The PCA contained placebo in Group 3 and patients received dexketoprofen 50 mg iv after awakening, repeated every 8 h. The IPI and NRS scores, total morphine consumption, and morphine related side-effects were recorded at 10 min, 1, 2, 6, 12, and 24 h post-operatively. The lowest IPI score, count of apnea, and desaturation events were recorded during the study period. RESULTS: The IPI scores were similar among the groups. Although a statistically significant difference was not observed among the groups the lowest IPI scores were observed in Group 1; apnea and desaturation counts were also higher in Group 1. Statistically significant differences were not observed among the groups in terms of pain scores, but were lower in Groups 1 and 2 compared to Group 3. CONCLUSION: Patient controlled analgesia with 0.5 mg morphine may be safe and effective for pain management following supratentorial craniotomies. Integrated pulmonary index can be used for detecting opioid-induced respiratory depression. Clinical Trials registration number: NCT02929147.

Drug Response Prediction by Globally Capturing Drug and Cell Line Information in a Heterogeneous Network.

One of the most important problem in personalized medicine research is to precisely predict the drug response for each patient. Due to relationships between drugs, recent machine learning-based methods have solved this problem using multi-task learning models. However, chemical relationships between drugs have not been considered. In addition, using very high dimensions of -omics data (e.g., genetic variant and gene expression) also limits the prediction power. A recent dual-layer network-based method was proposed to overcome these limitations by embedding gene expression features into a cell line similarity network and drug relationships in a chemical structure-based drug similarity network. However, this method only considered neighbors of a query drug and a cell line. Previous studies also reported that genetic variants are less informative to predict an outcome than gene expression. Here, we develop a novel network-based method, named GloNetDRP, to overcome these limitations. Besides gene expression, we used the genetic variant to build another cell line similarity network. First, we constructed a heterogeneous network of drugs and cell lines by connecting a drug similarity network and a cell line similarity network by known drug-cell line responses. Then, we proposed a method to predict the responses by exploiting not only the neighbors but also other drugs and cell lines in the heterogeneous network. Experimental results on two large-scale cell line data sets show that prediction performance of GloNetDRP on gene expression and genetic variant data is comparable. In addition, GloNetDRP outperformed dual-layer network- and typical multi-task learning-based methods.

Rationalizing Drug Response in Cancer Cell Lines.

Cancer cell lines (CCLs) play an important role in the initial stages of drug discovery allowing, among others, for the screening of drug candidates. As CCL panels continue to grow in size and diversity, many polymorphisms in genes encoding drug-metabolizing enzymes, transporters and drug targets, as well as disease-related genes have been linked to altered drug sensitivity. However, identifying the correlation between this variability and pharmacological responses remains challenging due to the heterogeneity of cancer biology and the intricate interplay between cell lines and drug molecules. Here, we propose a network-based strategy that exploits information on gene expression and somatic mutations of CCLs to group cells according to their molecular similarity. We then identify genes that are characteristic of each cluster and correlate their status with drug response. We find that CCLs with similar characteristic active network regions present specific responses to certain drugs, and identify a limited set of genes that might be directly involved in drug sensitivity or resistance.

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs).

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. ©2018 AACR.

[Analysis of the efficiency of antimicrobial treatment for community-acquired pneumonia in clinical practice]. / Analiz éffektivnosti antimikrobnoi terapii vnebol'nichnoi pnevmonii v klinicheskoi praktike.

AIM: To analyze actual drug consumption based on the defined daily dose (DDD analysis) and to analyze the utilization of drugs based on their proportion of the total defined daily doses (DU90% analysis) for the antimicrobial therapy of community-acquired pneumonia (CAP) in clinical practice at a hospital in Russia. MATERIAL AND METHODS: The investigation materials were the data of 117 case histories of male (51.3%) and female (48.7%) patients hospitalized with CAP at Nizhny Novgorod City Clinical Hospital Five in 2015. The investigation enrolled all the patients admitted to the hospital over the analyzed period. DDD analysis and DU90% analysis were used as study methods. RESULTS: DDD analysis and DU90% analysis of antimicrobial therapy for CAP were carried out at the hospital in clinical practice during a year. The annual number of defined daily doses (NDDD) for antimicrobial drugs, the number of defined daily doses per 100 bed-days (NDDD/100 bed-days), and a drug load (g) per 1000 CAP patients per day and per CAP patient per year were determined. The largest NDDD/year for CAP treatment with ceftriaxone was 376 g, or 43.43 NDDD/100 bed-days, which is much higher than that with other antimicrobial agents. The daily drug load of ceftriaxone per 1,000 CAP patients was 8.8 g, which exceeds that of moxifloxacin by 18.7 times, azithromycin and levofloxacin by 5 times, and ampicillin/sulbactam by 2.3 times. The daily drug load of ceftriaxone per CAP patient was 3.2 g, which exceeds that of of ampicillin/sulbactam by 2.3 times, levofloxacin and azithromycin by 5 times, and moxifloxacin by 19 times. CONCLUSION: It may be recommended that the proportion of cephalosporins as drugs that promote the rise of resistance in microbes and their production of extended-spectrum ß-lactamases should be further limited, the proportion of penicillins be extended, and the administered ampicillin/sulbactam be added, for example, by amoxicillin/clavulanate. Penicillins contribute to the rise of resistance to a lesser degree, and the use of two different penicillin molecules specified in the guidelines for the treatment of CAP will be able to slow the process further. By the same reasoning, it is also advisable to use cefuroxime (second-generation cephalosporins) along with ceftriaxone in patients in stable condition, without impairing vital functions.

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial.

BACKGROUND: Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen. METHODS: We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment. FINDINGS: Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders. INTERPRETATION: Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma. FUNDING: Novartis and Myeloma UK.