Lars L. Gustafsson

Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response

Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit–risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy–effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy–effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.

Multifaceted national and regional drug reforms and initiatives in ambulatory care in Sweden: global relevance

It is a continual challenge trying to improve the quality of prescribing while concurrently trying to address increasing pharmaceutical development, utilization and expenditure. National and regional reforms and initiatives in Sweden have moderated growth in ambulatory drug expenditure to 2.7% per annum in recent years despite increasing volumes. National reforms include mandatory generic substitution and value-based pricing alongside devolution of drug budgets to the regions. Regional initiatives include strengthening the role of the regional Drug and Therapeutic Committees, further budget devolution as well as strategies incorporating prescribing guidance and monitoring coupled with financial incentives. The extent and nature of the regional initiatives vary depending on their characteristics. In this article, we compare initiatives undertaken in two major counties, Stockholm and Östergötland, and their outcomes. Outcomes include annual drug budget savings while achieving agreed quality as well as increased adherence to prescribing targets and guidance; the latter associated with savings. Appraising these multifaceted reforms can provide guidance to other countries and regions in view of their diversity. Future steps must incorporate measures to improve the utilization of new expensive drugs, which should include horizon scanning and forecasting activities as well as post-launch activities involving monitoring of prescribing and registries. This may well require cooperation with other European countries.

Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications

Aim: the aim of this article was to evaluate the influence of different demand-side measures to enhance the prescribing of generics in ambulatory care based on cross-national comparisons. Methods: an observational retrospective study was conducted using administrative databases from across Europe, documenting changes in reimbursed utilization and expenditure of different proton pump inhibitors (PPIs) and statins between 2001 and 2007, alongside different reforms to enhance prescribing efficiency. Utilization was converted to defined daily doses (DDDs) and expenditures were converted to euros. Demand-side measures were collated under the ‘4 Es’ – education, engineering, economics and enforcement – to enable comparisons on the nature and intensity of reforms between countries. Results: there were considerable differences in the utilization of generics and patent-protected PPIs and statins among Western European countries. Decreased utilization of omeprazole and simvastatin, alongside increased utilization of esomeprazole, atorvastatin and rosuvastatin, was seen in countries with limited demand-side measures to counteract commercial pressures. Prescribing restrictions, or a combination of education, prescribing targets and financial incentives, had the greatest influence on enhancing the utilization of omeprazole and simvastatin. For example, there was a threefold reduction in the utilization of atorvastatin in Austria following prescribing restrictions. Multiple demand-side interventions generally had a greater influence than single interventions, with the impact appearing additive. Multiple interventions coupled with initiatives to lower prices of generics considerably enhanced prescribing efficiency. Conclusion: this cross-national study has demonstrated considerable variation in the utilization and expenditure of PPIs and statins across Europe, providing opportunities to further improve prescribing efficiency. The ‘4 Es’ do provide an understandable methodology to document and compare the influence of different demand-side measures, with the influence varying by their extent and intensity. Further reforms are essential given current financial pressures. Consequently, further research will concentrate on the potential to develop a scoring system to help predict the possible impact of different demand-side measures on future utilization patterns.

4??-Hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians

Objectives To study the potential endogenous marker of CYP3A activity, 4&bgr;-hydroxycholesterol, and its relation to sex and the CYP3A5 geno/haplotypes and compare with CYP3A4/5 catalyzed 3-hydroxylation of quinine in the three major races. Methods The plasma concentration of 4&bgr;-hydroxycholesterol was measured in healthy Tanzanians (n=138), Swedes (n=161) and Koreans (n=149) by gas chromatography–mass spectrometry. The metabolic ratio of quinine/3-hydroxyquinine in plasma 16-h post dose was determined by high performance liquid chromatography, previously reported in Tanzanians and Swedes, and now also in Koreans. The participants were genotyped for relevant alleles of CYP3A5. Results The mean plasma concentrations of 4&bgr;-hydroxycholesterol in Koreans, Swedes and Tanzanians were 29.3, 26.8 and 21.9 ng/ml, respectively (P<0.01 between all three populations). Within all three populations there were significant differences in 4&bgr;-hydroxycholesterol levels between the CYP3A5 genotypes. Women had higher concentrations than men, but the difference was only significant in Tanzanians (P<0.001) and Koreans (P<0.00001). The quinine/3-hydroxyquinine metabolic ratio was significantly different in all three populations with the highest CYP3A activity in Koreans and the lowest in Tanzanians. Korean women had a lower metabolic ratio than men (P<0.00001). Significant correlations between 4&bgr;-hydroxycholesterol and quinine 3-hydroxylation were found in Tanzanians and Koreans. Conclusion Clear differences in the activity of both CYP3A4 and CYP3A5 were shown in the three major human races. Both 4&bgr;-hydroxycholesterol and quinine/3-hydroxyquinine metabolic ratio showed a higher CYP3A activity in women than in men. The results give strong evidence that the plasma concentration of 4&bgr;-hydroxycholesterol may be used as an endogenous marker of CYP3A activity (CYP3A4+5).

Malaria rapid testing by community health workers is effective and safe for targeting malaria treatment: randomised cross-over trial in Tanzania.

Background Early diagnosis and prompt, effective treatment of uncomplicated malaria is critical to prevent severe disease, death and malaria transmission. We assessed the impact of rapid malaria diagnostic tests (RDTs) by community health workers (CHWs) on provision of artemisinin-based combination therapy (ACT) and health outcome in fever patients. Methodology/Principal Findings Twenty-two CHWs from five villages in Kibaha District, a high-malaria transmission area in Coast Region, Tanzania, were trained to manage uncomplicated malaria using RDT aided diagnosis or clinical diagnosis (CD) only. Each CHW was randomly assigned to use either RDT or CD the first week and thereafter alternating weekly. Primary outcome was provision of ACT and main secondary outcomes were referral rates and health status by days 3 and 7. The CHWs enrolled 2930 fever patients during five months of whom 1988 (67.8%) presented within 24 hours of fever onset. ACT was provided to 775 of 1457 (53.2%) patients during RDT weeks and to 1422 of 1473 (96.5%) patients during CD weeks (Odds Ratio (OR) 0.039, 95% CI 0.029–0.053). The CHWs adhered to the RDT results in 1411 of 1457 (96.8%, 95% CI 95.8–97.6) patients. More patients were referred on inclusion day during RDT weeks (10.0%) compared to CD weeks (1.6%). Referral during days 1–7 and perceived non-recovery on days 3 and 7 were also more common after RDT aided diagnosis. However, no fatal or severe malaria occurred among 682 patients in the RDT group who were not treated with ACT, supporting the safety of withholding ACT to RDT negative patients. Conclusions/Significance RDTs in the hands of CHWs may safely improve early and well-targeted ACT treatment in malaria patients at community level in Africa. Trial registration ClinicalTrials.gov NCT00301015

Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization

Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous system. Clinical pain states with allodynia in connection with longstanding superficial wounds have, however, not been reported in the literature. In this case a chronic pain state developed in a previously healthy 17-year-old girl in and around a persistently suppurating appendectomy wound. There was no spontaneous pain but pronounced allodynia in the wound and in the surrounding skin. Quantitative thermal tests showed abnormal thresholds for several sensory modalities confirming abnormal processing of sensory input from the involved area. The pattern of sensory abnormalities evaluated with thermal testing changed transiently and the allodynia diminished during a phentolamine block. Since the pain responded poorly to opioids and ketamine has been reported to reduce allodynia, it was administered in a sub-dissociative bolus dose during wound dressing. The wound was essentially unchanged after treatment for 3 months but the allodynia and sensory aberrations had decreased significantly. We interpret these results as a de-sensitizing effect in the long term of repeated NMDA-receptor blockade by ketamine in a chronic pain state, with indications of central sensitization, partially maintained by sympathetic activity.

Central nervous system effects of subdissociative doses of (S)‐ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)‐ketamine were measured in a randomized, double‐blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)‐[N‐methyl‐11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N‐methyl‐D‐aspartate receptor complexes. A significant and dose‐dependent reduction of binding was measured as a result of displacement of (S)‐[N‐methyl‐11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)‐ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)‐ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)‐ketamine, measured with positron emission tomography, can be related directly to drug effects.

A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans

AIMS Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.

Methadone, ciprofloxacin, and adverse drug reactions.

Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 and CYP3A4 activity, two of the cytochrome p450 isozymes involved in the metabolism of methadone.

SFINX—a drug-drug interaction database designed for clinical decision support systems

ObjectiveThe aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions.MethodsKey elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions.ResultsSFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content.ConclusionSFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.