Gunnar Alvan

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.

Muscle toxicity with statins.

Statins rarely cause serious muscle toxicity and rhabdomyolysis. The aim of our investigation was to identify and quantify potential risk factors for statin‐induced rhabdomyolysis.

The conscientious judgement of a DSMB – statistical stopping rules re-examined

ObjectiveIn the light of the recent failure of a large cardiovascular mortality and morbidity study with torcetrapib, we have undertaken a post hoc review of the decisions taken by the Data and Safety Monitoring Board (DSMB) in that study. A number of other studies in which complex decisions were made by DSMBs are also reviewed.ResultsThe examples illustrate the complexities involved in the decision-making process by DSMBs and indicate that too much reliance on formal statistical stopping rules should be avoided due to a risk of delaying the identification of an unacceptable emergent safety signal.MethodsThe review was based on information submitted by the sponsors of the studies to the Medical Products Agency.ConclusionsMultiple approaches to assessing the efficacy and safety in clinical trials need to be considered in order to facilitate early stopping of clinical trials with a negative risk benefit balance. Such systems may, for example, include the use of p-value flags and/or a complementary statistical analysis of the likelihood of achieving the study objective based on the data obtained to date.

The effect of intravenously administered mexiletine on tinnitus-a pilot study

The effect of intravenously administered mexiletine on subjective tinnitus and hearing was studied in six patients, who initially responded positively to lidocaine. Distinct mexiletine-induced decreases in tinnitus loudness were demonstrated in three subjects, as reflected by maximum VAS (visual analogue scale) level reduction of 34%, 95%, and 100%, respectively. One subject reported change in tinnitus pitch, another one showed a slight (18% on VAS) tinnitus reduction, and one subject disclosed no effect. Side effects were seen only during one of seven infusions. Mexiletine induced shifts in pure-tone threshold, transient evoked otoacoustic emission, and acoustic reflex threshold, probably reflecting a reversible interference in the function of organ of Corti. The concentration effect relationship remained unclear and no general ‘therapeutic’ level could be identified. This study confirms the effect of mexiletine on the auditory function and its potential as a possible therapeutic agent or a model for further development in tinnitus pharmacotherapy.

A Swedish Regulatory Perspective on European Risk Management

Worldwide, drug regulation safety requirements in the past can be seen as responses to major drug disasters, such as thalidomide or diethylstilbestrol. In the light of the more recent drug disasters, the public is less willing to accept risk associated with drug therapy. Increased emphasis has to be placed on the proactive identification of potential safety issues with new drugs at the earliest possible occasion, and before large populations have already been exposed to the drug. The concept of balance between potential benefit and risk also has to be communicated more strongly.This article presents an overview of spontaneous reporting systems and signal detection and evaluation. It also discusses regulatory issues and risk management with an emphasis on the new European Community system. A number of new initiatives and obligations are introduced that are handled by the European regulatory agencies.

Concentration–Response Relationship of Hearing Impairment Caused by Quinine and Salicylate: Pharmacological Similarities but Different Molecular Mechanisms

This review has the purpose to summarize concentration-effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine-induced increase in hearing threshold and its recovery can be analysed according to the psychophysical power function. The power function is a special case of the Hill equation when the stimulus (e.g. a drug concentration) is exceedingly small compared with the concentration that would elicit a half-maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence the presence, magnitude, and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self-attained most comfortable speech level and the acoustic stapedius reflex are not affected, that is the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but performed with different molecular mechanisms.

Compliance Analysis as Additional Evidence for Efficacy in Clinical Trials: Perspectives of the Swedish Medical Products Agency

Deficient adherence to trial protocols including dosing errors introduces uncertainty about the reliability of clinical trial results. Traditional ways of measuring compliance have been challenged since studies using electronic monitoring to register opening of medication containers have revealed that patient reporting and residual tablet counting tend to overestimate compliance with dosing regimens. Application to the Medical Products Agency for approval of all clinical trials performed in Sweden on medicines involving human subjects has been obligatory since 1984. The number of applications has ranged from 394 to 675 per year. Among over 1,000 clinical trial applications between May 2004 and February 2008, compliance or adherence was mentioned in the study objectives of only two applications. Clinical trial applications that combine adherence information with clinical outcome are still rare in Sweden. Phase 3 clinical trials are designed to provide sufficient evidence of efficacy to support marketing authorization. Patients are typically analyzed according to assigned group (intention to treat principle) rather than according to actual treatment received in order to ensure that an identified treatment effect is due to the treatment itself and not a result of postrandomization bias. Taking account of compliance information is therefore mainly considered as supportive evidence except for noninferiority clinical trials. However, electronic capturing of compliance information in clinical trials may have an important role in advancing our understanding of the relationship between drug dose or concentration and therapeutic efficacy or adverse reactions. Ways to optimize information from clinical trials are encouraged from a Swedish regulatory perspective and are expected to increase study efficiency.