Chloroquine and hydroxychloroquine for COVID-19: Perspectives on their failure in repurposing.

WHAT IS KNOWN AND OBJECTIVE: Non-clinical studies suggest that chloroquine (CQ) and hydroxychloroquine (HCQ) have antiviral activities. Early clinical reports of successful HCQ-associated reduction in viral load from small studies in COVID-19 patients spurred a large number of national and international clinical trials to test their therapeutic potential. The objective of this review is to summarize the current evidence on the safety and efficacy of these two agents and to provide a perspective on why their repurposing has hitherto failed. METHODS: Published studies and rapidly emerging data were reviewed to gather evidence on safety and efficacy of CQ and HCQ in patients with COVID-19 infection or as prophylaxis. The focus is on clinically relevant efficacy endpoints and their adverse effects on QT interval. RESULTS AND DISCUSSION: At the doses used, the two agents, given alone or with azithromycin (AZM), are not effective in COVID-19 infection. The choice of (typically subtherapeutic) dosing regimens, influenced partly by "QT-phobia," varied widely and seems anecdotal without any pharmacologically reliable supporting clinical evidence. A substantial proportion of patients receiving CQ/HCQ/AZM regimen developed QTc interval prolongation, many with absolute QTc interval exceeding the potential proarrhythmic threshold, but very few developed proarrhythmia. WHAT IS NEW AND CONCLUSION: The strategy to repurpose CQ/HCQ to combat COVID-19 infection is overshadowed by concerns about their QT liability, resulting in choice of potentially subtherapeutic doses. Although the risk of QT-related proarrhythmia is real, it is low and manageable by careful monitoring. Recent discontinuation of HCQ from at least four large studies effectively marks the end of efforts at repurposing of CQ or HCQ for COVID-19 infection. This episode leaves behind important questions on dose selection and risk/benefit balance in repurposing drugs generally.

Genotype-guided warfarin therapy: Still of only questionable value two decades on.

WHAT IS KNOWN AND OBJECTIVE: Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so. METHODS: Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. RESULTS AND DISCUSSION: Critical examination of major warfarin pharmacogenetic studies identified a number of methodological concerns such as marked variations in study designs with different variously-defined measures of outcome. Genotype testing involved only a limited number of CYP2C9/VKORC1 alleles. Claims of benefits of genotyping are based almost exclusively on INR-related parameters which are known to be highly time-labile and of limited value in predicting clinical risk or benefit. This is evidenced by lack of any significant effect of genotyping on rates of bleeding or thromboembolic events. Neither have the effects of potential phenoconversion or medication non-adherence in study populations been adequately investigated. Although the effect of ethnicity/race is now better characterised, studies lack the power to determine whether any benefits claimed are indication-sensitive. WHAT IS NEW AND CONCLUSION: Since 60% of inter-individual variability in warfarin dose/response is due to other factors (many of which are non-genetic), expectations of eliminating this variability simply by CYP2C9/VKORC1 genotyping are over-optimistic and efforts cost-ineffective. Real-world studies have not always corroborated trials-based claims of clinical benefit. It is time to consider redirecting scarce resources away from the study of warfarin pharmacogenetics to pharmacogenetic research of potentially greater clinical relevance.

Safety and Tolerability of Histone Deacetylase (HDAC) Inhibitors in Oncology.

Histone deacetylases (HDACs) are expressed at increased levels in cells of various malignancies, and the use of HDAC inhibitors has improved outcomes in patients with haematological malignancies (T-cell lymphomas and multiple myeloma). However, they are not as effective in solid tumours. Five agents are currently approved under various jurisdictions, namely belinostat, chidamide, panobinostat, romidepsin and vorinostat. These agents are associated with a range of class-related and agent-specific serious and/or severe adverse effects, notably myelosuppression, diarrhoea and various cardiac effects. Among the cardiac effects are ST-T segment abnormalities and QTc interval prolongation of the electrocardiogram, isolated cases of atrial fibrillation and, in rare instances, ventricular tachyarrhythmias. In order to improve the safety profile of this class of drugs as well as their efficacy in indications already approved and to further widen their indications, a large number of newer HDAC inhibitors with varying degrees of HDAC isoform selectivity have been synthesised and are currently under clinical development. Preliminary evidence from early studies suggests that they may be effective in non-haematological cancers as well when used in combination with other therapeutic modalities, but that they too appear to be associated with the above class-related adverse effects. As the database accumulates, the safety, efficacy and risk/benefit of the newer agents and their indications will become clearer.

Safety and Tolerability of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in Oncology.

Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) have dramatically improved progression-free survival in non-small-cell lung cancer (NSCLC) patients who carry sensitizing EGFR-activating mutations and in patients with breast and pancreatic cancers. However, EGFR-TKIs are associated with significant and disabling undesirable effects that adversely impact on quality of life and compliance. These effects include dermatological reactions, diarrhoea, hepatotoxicity, stomatitis, interstitial lung disease and ocular toxicity. Each individual EGFR-TKI is also associated with additional adverse effect(s) that are not shared widely by the other members of its class. Often, these effects call for dose reduction, treatment discontinuation or pharmacotherapeutic intervention. Since dermatological effects result from on-target effects on wild-type EGFR, rash is often considered to be a biomarker of efficacy. A number of studies have reported better outcomes in patients with skin reactions compared with those without. This has led to a 'dosing-to-rash' strategy to optimize therapeutic outcomes. Although conceptually attractive, there is currently insufficient evidence-based support for this strategy. While skin reactions following EGFR-TKIs are believed to result from an effect on wild-type EGFR, their efficacy is related to effects on mutant variants of EGFR. It is noteworthy that newer EGFR-TKIs that spare wild-type EGFR are associated with fewer dermatological reactions. Furthermore, secondary mutations such as T790M in exon 20 often lead to development of resistance to the clinical activity and efficacy of first- and second-generation EGFR-TKIs. This has stimulated the search for later-generations of EGFR-TKIs with the ability to overcome this resistance and with greater target selectivity to spare wild-type EGFR in expectations of an improved safety profile. However, available data reviewed herein indicate that not only are these newer agents associated with the aforementioned adverse effects typical of earlier agents, but they are also susceptible to resistance due to tertiary mutations, most frequently C797S. At least three later-generation EGFR-TKIs, canertinib, naquotinib and rociletinib, have been discontinued from further development in NSCLC following concerns about their safety and risk/benefit.

Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology.

Activation of phosphatidylinositol-3-kinase (PI3K) and downstream signalling by AKT/mammalian target of rapamycin (mTOR) modulates cellular processes such as increased cell growth, cell proliferation and increased cell migration as well as deregulated apoptosis and oncogenesis. The PI3K/AKT/mTOR pathway (particularly Class I PI3K isoforms) is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology. Inhibitors of PI3K also have the potential to restore sensitivity to other modalities of treatments when administered as part of combination regimens. Although many PI3K inhibitors have reached different stages of clinical development, only two (idelalisib and copanlisib) have been currently approved for use in the treatment of B cell lymphoma and leukaemias. While these two agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. They also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Not surprisingly, therefore, many new PI3K inhibitors with a varying degree of target selectivity have been synthesised in expectations of improved safety and efficacy, and are currently under clinical investigations for use in a variety of solid tumours as well as haematological malignancies. However, evidence from early clinical trials, reviewed herein, suggests that these newer agents are also associated not only with class-related but also other serious and unexpected adverse effects. Their risk/benefit evaluations have resulted in a number of them being discontinued from further development. Cumulative experience with the use of PI3K inhibitors under development suggests that, compared with their use as monotherapy, combining them with other anticancer therapies may be a more effective strategy in improving current standard-of-care and clinical outcomes in cancers beyond haematological cancers. For example, combination of alpelisib with fulvestrant has recently demonstrated unexpectedly superior efficacy compared to fulvestrant alone. Furthermore, the immunomodulatory activity of PI3Kδ and PI3Kγ inhibitors also provides unexpected opportunities for their use in cancer immunotherapy, as is currently being tested in several clinical trials.

Metamizole (dipyrone)-induced agranulocytosis: Does the risk vary according to ethnicity?

WHAT IS KNOWN AND OBJECTIVE: Based on spontaneous reports from Spain, it is claimed that the British, Irish and Scandinavians are at a greater risk of dipyrone-induced agranulocytosis. This report examines the evidence. COMMENT: Although interethnic differences in drug response are well known, there are no reliable epidemiologic data to support the above claim. Available information on chlorpromazine suggests variable ethnic sensitivities to drug-induced agranulocytosis. Agranulocytosis induced by at least four drugs has been associated with variant HLA alleles. Preliminary evidence also suggests that the presence of specific variant HLA alleles may sensitize individuals to dipyrone-induced agranulocytosis. There are historical reasons to suspect that the three populations referred to may share some key genetic features, including the potentially culprit variant HLA alleles, that predispose them to dipyrone-induced agranulocytosis. WHAT IS NEW AND CONCLUSION: The possibility that the British, Irish and Scandinavians show higher susceptibility than other populations to dipyrone-induced agranulocytosis cannot be ruled out. If this complication is linked to specific HLA allele(s), populations with higher frequency of variant HLA allele(s) may be at a greater risk. If confirmed, screening for the risk allele may be useful in reducing the risk of dipyrone-induced agranulocytosis.

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead.

WHAT IS KNOWN AND OBJECTIVE: In order to expedite the availability of drugs to treat cancers in a cost-effective manner, repurposing of old drugs for oncological indications is gathering momentum. Revolutionary advances in pharmacology and genomics have demonstrated many old drugs to have activity at novel antioncogenic pharmacological targets. We decided to investigate whether prospective studies support the promises of nonclinical and retrospective clinical studies on repurposing three old drugs, namely metformin, valproate and astemizole. METHODS: We conducted an extensive literature search through PubMed to gather representative nonclinical and retrospective clinical studies that investigated the potential repurposing of these three drugs for oncological indications. We then searched for prospective studies aimed at confirming the promises of retrospective data. RESULTS AND DISCUSSION: While evidence from nonclinical and retrospective clinical studies with these drugs appears highly promising, large scale prospective studies are either lacking or have failed to substantiate this promise. We provide a brief discussion of some of the challenges in repurposing. Principal challenges and obstacles relate to heterogeneity of cancers studied without considering their molecular signatures, trials with small sample size and short duration, failure consider issues of ethnicity of study population and effective antioncogenic doses of the drug studied. WHAT IS NEW AND CONCLUSION: Well-designed prospective studies demonstrating efficacy are required for repurposing old drugs for oncology indications, just as they are for new chemical entities for any indication. Early and ongoing interactions with regulatory authorities are invaluable. We outline a tentative framework for a structured approach to repurposing old drugs for novel indications in oncology.

Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty.

Prenylamine, an antianginal agent marketed since early 1960, became the first casualty of QT interval related proarrhythmias in 1988 when it was withdrawn from the market. The period of its synthesis and marketing is of particular interest since it antedated, first, any serious clinical safety concern regarding drug-induced prolongation of the QT interval which was, in fact, believed to be an efficient antiarrhythmic mechanism; second, the first description of torsade de pointes as a unique proarrhythmia, typically associated with prolonged QT interval; and third, the discovery and recognition of calcium antagonism as an important cardiovascular therapeutic strategy. This review, 30 years almost to the day following its withdrawal, provides interesting perspectives on clinical, pharmacological and regulatory outcomes that followed. Prenylamine underscored torsadogenic potential of other early antianginal drugs on the market at that time and identified QT-related proarrhythmias as a much wider major public health issue of clinical and regulatory concern. This resulted in various guidelines for early identification of this potentially fatal risk. Application of these guidelines would have readily identified its proarrhythmic potential. Prenylamine also emphasized differences in drug responses between men and women which subsequently galvanized extensive research into sex-related differences in pharmacology. More importantly, however, investigations into the mechanisms of its action paved the way to developing modern safe and effective calcium antagonists that are so widely used today in cardiovascular pharmacotherapy.

Precision medicine: does ethnicity information complement genotype-based prescribing decisions?

Inter-ethnic differences in drug response are all too well known. These are underpinned by a number of factors, including pharmacogenetic differences across various ethnic populations. Precision medicine relies on genotype-based prescribing decisions with the aim of maximizing efficacy and mitigating the risks. When there is no access to genotyping tests, ethnicity is frequently regarded as a proxy of the patient's probable genotype on the basis of overall population-based frequency of genetic variations in the ethnic group the patient belongs to, with some variations being ethnicity-specific. However, ever-increasing transcontinental migration of populations and the resulting admixing of populations have undermined the utility of self-identified ethnicity in predicting the genetic ancestry, and therefore the genotype, of the patient. An example of the relevance of genetic ancestry of a patient is the inadequate performance of European-derived pharmacogenetic dosing algorithms of warfarin in African Americans, Brazilians and Caribbean Hispanics. Consequently, genotyping a patient potentially requires testing for all known clinically actionable variants that the patient may harbour, and new variants that are likely to be identified using state-of the art next-generation sequencing-based methods. Furthermore, self-identified ethnicity is associated with a number of ethnicity-related attributes and non-genetic factors that potentially influence the risk of phenoconversion (genotype-phenotype discordance), which may adversely impact the success of genotype-based prescribing decisions. Therefore, while genotype-based prescribing decisions are important in implementing precision medicine, ethnicity should not be disregarded.

Importance of Publishing Adverse Drug Reaction Case Reports: Promoting Public Health and Advancing Pharmacology and Therapeutics.

This article, which encourages physicians to publish case reports of adverse drug reactions (ADRs), is a review of how well-documented published case reports have contributed to promoting public safety and health and thus served to advance basic pharmacology. The origin of a number of regulatory guidelines can ultimately be traced to safety concerns triggered by such reports. It illustrates how case reports of ADRs, when coupled with simultaneous monitoring of drug pharmacokinetics, have also led to further investigations resulting in major advances in pharmacology, especially pharmacogenetics, mechanisms of drug-drug interactions and modulation of drug metabolism during inflammatory co-morbidities. Published case reports differ significantly from spontaneous case reports since they enjoy quality-compliant peer review and an immediate wider visibility among the readership, triggering others to report similar cases, and ultimately leading to prescribing restrictions on or withdrawals of the drug from the market depending on the risk. Therefore, the reporter should not be discouraged by (a) the unusual or bizarre nature of the reaction; (b) the interval, however long, from commencing drug administration to the onset of the suspected reaction; (c) however well-known the drug or the period for which it has been on the market; and (d) any pressure not to publish. Case reports should be published in reputable journals that are searchable through databases such as PubMed.

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies.

BACKGROUND AND PURPOSE: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. EXPERIMENTAL APPROACH: Nonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro-arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell-derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B-recommended assays included in vitro hERG (KV 11.1) channels, in vivo dog studies with follow-up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro-arrhythmia model. KEY RESULTS: Both sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT-liability or pro-arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late INa reducing activities at high concentrations, which resulted in pitolisant reducing dofetilide-induced early after-depolarizations (EADs) in the ICH S7B studies. Studies in stem cell-derived human cardiomyocytes with dofetilide or E-4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the ion channel effects measured are consistent with results from both the stem cell-derived cardiomyocytes and rabbit Purkinje fibres and categorized pitolisant as a drug with low torsadogenic potential. Results from the two sets of nonclinical studies correlated well with those from two clinical QT studies. CONCLUSIONS AND IMPLICATIONS: Our findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro-arrhythmia models when the results from CiPA studies are ambiguous.

Anti-Angiogenic Tyrosine Kinase Inhibitors and Reversible Posterior Leukoencephalopathy Syndrome: Could Hypomagnesaemia Be the Trigger?

Reversible posterior leukoencephalopathy syndrome (RPLS), also known frequently as posterior reversible encephalopathy syndrome (PRES), is a characteristic acute neuro-radiology syndrome with clinical presentation that typically includes acute hypertension, seizures and other neurological symptoms and signs. Many patients with RPLS have (a history of) pre-existing hypertension and in receipt of diuretics. It is being diagnosed more frequently and in association with an increasing number of morbidities and medications. Drugs most frequently implicated are immunosuppressant drugs and anticancer agents, including a number of anti-angiogenic tyrosine kinase inhibitors (TKIs). Hypomagnesaemia is a frequent finding at presentation in RPLS patients, which is known to lead to or aggravate hypertension. Pre-eclampsia, a variant of RPLS, responds effectively to intravenous magnesium. Cyclosporin, tacrolimus and some TKIs that induce RPLS are also known to give rise to both hypertension and hypomagnesaemia. This raises an interesting hypothesis that hypomagnesaemia may play a contributory role in triggering RPLS in some patients by acutely raising the blood pressure further. Additional systematic studies are required to test this hypothesis. If the hypothesis is confirmed, hypomagnesaemia offers an effective target for risk mitigation and prevention of RPLS in patients identified at risk.

Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity?

Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy.

Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas.

Since the approval of the first molecularly targeted tyrosine kinase inhibitor (TKI), imatinib, in 2001, TKIs have heralded a new era in the treatment of many cancers. Among their innumerable adverse effects, interstitial lung disease (ILD) is one of the most serious, presenting most frequently with dyspnea, cough, fever, and hypoxemia, and often treated with steroids. Of the 28 currently approved TKIs, 16 (57 %) are reported to induce ILD with varying frequency and/or severity. The interval from drug administration to onset of ILD varies between patients and between TKIs, with no predictable time course. Its incidence is variously reported to be approximately 1.6-4.3 % in Japanese populations and 0.3-1.0 % in non-Japanese populations. The mortality rate is in the range of 20-50 %. Available evidence (primarily following the use of erlotinib and gefitinib in Japan because of the unique susceptibility of that population) has identified a number of susceptibility and prognostic risk factors (male sex, a history of smoking, and pre-existing pulmonary fibrosis being the main ones). Although the precise mechanism is not understood, collective evidence suggests that immune factors may be involved. If TKI-induced ILD is confirmed by thorough evaluation of the patient and exclusion of other causes, management is supportive, and includes discontinuation of the culprit TKI and administration of steroids. Discontinuing the culprit TKI presents a clinical dilemma because the diagnosis of TKI-induced ILD in a patient with pre-existing pulmonary fibrosis can be challenging, the patient may have TKI-responsive cancer with no suitable alternative, and switching to an alternative agent, even if available, carries the risk of the patient experiencing other toxic effects. Preliminary evidence suggests that therapy with the culprit TKI may be continued under steroid cover and/or at a reduced dose. However, this approach requires careful individualized risk-benefit analysis and further clinical experience.

Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist.

OBJECTIVE: The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study. METHODS: The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis. Results from the two studies were compared. RESULTS: In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study. CONCLUSION: Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.

CYP450 genotype and pharmacogenetic association studies: a critical appraisal.

Despite strong pharmacological support, association studies using genotype-predicted phenotype as a variable have yielded conflicting or inconclusive evidence to promote personalized pharmacotherapy. Unless the patient is a genotypic poor metabolizer, imputation of patient's metabolic capacity (or metabolic phenotype), a major factor in drug exposure-related clinical response, is a complex and highly challenging task because of limited number of alleles interrogated, population-specific differences in allele frequencies, allele-specific substrate-selectivity and importantly, phenoconversion mediated by co-medications and inflammatory co-morbidities that modulate the functional activity of drug metabolizing enzymes. Furthermore, metabolic phenotype and clinical outcomes are not binary functions; there is large intragenotypic and intraindividual variability. Therefore, the ability of association studies to identify relationships between genotype and clinical outcomes can be greatly enhanced by determining phenotype measures of study participants and/or by therapeutic drug monitoring to correlate drug concentrations with genotype and actual metabolic phenotype. To facilitate improved analysis and reporting of association studies, we propose acronyms with the prefixes 'g' (genotype-predicted phenotype) and 'm' (measured metabolic phenotype) to better describe this important variable of the study subjects. Inclusion of actually measured metabolic phenotype, and when appropriate therapeutic drug monitoring, promises to reveal relationships that may not be detected by using genotype alone as the variable.

Establishing assay sensitivity in QT studies: experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study.

OBJECTIVE: To compare the effect of moxifloxacin as a positive control in a single ascending dose (SAD) study with that in a thorough QT (TQT) study. METHODS: Moxifloxacin was used as a positive control in a SAD study and a TQT study during the evaluation of the QT liability of a new drug. The SAD study had enrolled 24 males and the TQT study 25 males. Both studies intensively monitored electrocardiograms (ECGs) and pharmacokinetic sampling. Effect of moxifloxacin on QTc interval was analysed in each study by intersection union test (IUT) and by exposure-response (ER) analysis and the results compared. Cost-effectiveness of this approach was computed. RESULTS: Analysis by IUT revealed that the maximum mean (90 % confidence interval (CI)) placebo-corrected change from baseline (ΔΔQTcF) in the SAD study and the TQT study were remarkably similar (10.7 (6.5; 14.9) ms vs. 9.09 (6.20; 11.98) ms, respectively). In both studies, assay sensitivity was established by the 90 % lower bound exceeding 5 ms. ER analysis revealed the slopes in both studies to be significantly different from zero and comparable. Bootstrap-predicted effects of moxifloxacin at geometric mean concentrations of ~3000 ng/mL were 8.19 (90 % CI 5.86; 10.7) ms in the SAD study and 7.33 (90 % CI 5.69; 9.70) ms in the TQT study. CONCLUSION: Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion.