Incidence of fatal adverse drug reactions: a population based study

Aims

To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

Methods

Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

Results

Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

Conclusions

The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

What is already known about this subject

• Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.
• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.
• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

What this study adds

• Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.
• Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.
• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

     

Adherence to statin or aspirin or both in patients with established cardiovascular disease: exploring healthy behaviour vs. drug effects and 10-year follow-up of outcome

Aims

To characterize adherence in patients with established cardiovascular disease taking statins and aspirin and to estimate the effects of adherence due to health behaviour, a lack of beneficial drug effect, or both on recurrence of cardiovascular disease or all-cause mortality over 10 years.

Methods

A population-based cohort study using a record-linkage database in Tayside, Scotland. Subjects with cardiovascular disease (n = 7657; 4185 aspirin-alone cohort, 671 statin-alone cohort and 2801 combination use cohort) were studied between 1993 and 2003. The effects of adherence on recurrence of cardiovascular disease or mortality were assessed using Poisson regression model.

Results

In subjects taking both aspirin and statins, those adherent to statins but not aspirin had a lower risk of recurrence [adjusted risk ratio (RR) 0.64; 95% confidence interval 0.49, 0.82], but those adherent to aspirin but not statins has no such effect (adjusted RR 0.91; 0.72, 1.15), suggesting that adherence behaviour alone was not responsible for the beneficial effect. Within the group adherent to aspirin, ≥80% adherence to statins was associated with reduced recurrence compared with those poorly adherent (adjusted RR 0.76; 0.62, 0.94), but no such effect of aspirin was seen in those adherent to statins. Similar results were found for all-cause mortality.

Conclusions

Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients. Adverse outcome is more likely to be driven by foregone drug benefits.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Aspirin and statins are widely-used drugs in patients with cardiovascular disease.
• There is less information on healthy behaviour vs. drug effects.

WHAT THIS STUDY ADDS

• Long-term adherence to aspirin and statin treatments in patients with established cardiovascular disease has been investigated.
• Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients.

     

A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

AIMS

To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding.

METHODS

The French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR).

RESULTS

Hypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6, 8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively).

CONCLUSION

A signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use.
• Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used.
• Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding.

WHAT THIS STUDY ADDS

• An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database.
• This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication.
• The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users.

     

Estimation of the impact of noncompliance on pharmacokinetics: an analysis of the influence of dosing regimens

AIMS

To determine whether, for oxybutynin and risperidone, drug exposure is better with less frequent dosing regimens than with regimens that require more frequent dosing.

METHODS

Pharmacokinetic models of oxybutynin (5 mg twice-daily and 10 mg once-daily) and risperidone (2 mg once-daily orally and 25 mg fortnightly intramuscular injection) were developed. Simulations of multiple doses were performed by use of stochastic models of dose-taking compliance and clinic visit attendance.

RESULTS

At therapeutic concentrations and with typical patterns of noncompliance, intramuscular injections of risperidone resulted in a 41% (SD 12%) greater pharmacokinetic coverage than the oral dose, 76% (SD 10%) vs. 35% (SD 7%). No discernable differences were evident between once- and twice-daily formulations of oxybutynin, 29.2% (SD 10%) vs. 29.0% (SD 13%).

CONCLUSIONS

For equivalent doses for each drug, the longer acting preparation of risperidone, but not oxybutynin, is pharmacokinetically more forgiving of noncompliance than the shorter acting counterparts. Further analysis is required to confirm whether these observations are valid clinically.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Patient compliance is better with formulations that require less frequent dosing than with formulations that require more frequent dosing.
• Intramuscular risperidone and long-acting oxybutynin are two examples of medicines reformulated for less frequent dosing.
• However, it is not clear whether better compliance with less frequent dosing regimens translates to improved therapeutic outcome.

WHAT THIS STUDY ADDS

• At equivalent daily doses and typical patterns of compliance, fortnightly intramuscular depot administrations of risperidone provide better pharmacokinetic coverage than once-daily oral dosing.
• Once-daily dosing of oxybutynin is no better at maintaining pharmacokinetic exposure than twice-daily dosing at half strength.
• The use of simulated compliance data as input to pharmacokinetic models is useful to assess the impact of noncompliance on internal drug exposure.

     

Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction

AIMS

The aim of this study was to explore and optimize the in vitro and in silico approaches used for predicting clinical DDIs. A data set containing clinical information on the interaction of 20 Pfizer compounds with ketoconazole was used to assess the success of the techniques.

METHODS

The study calculated the fraction and the rate of metabolism of 20 Pfizer compounds via each cytochrome P450. Two approaches were used to determine fraction metabolized (f_m); 1) by measuring substrate loss in human liver microsomes (HLM) in the presence and absence of specific chemical inhibitors and 2) by measuring substrate loss in individual cDNA expressed P450s (also referred to as recombinant P450s (rhCYP)) The fractions metabolized via each CYP were used to predict the drug–drug interaction due to CYP3A4 inhibition by ketoconazole using the modelling and simulation software SIMCYP®.

RESULTS

When in vitro data were generated using Gentest supersomes, 85% of predictions were within two-fold of the observed clinical interaction. Using PanVera baculosomes, 70% of predictions were predicted within two-fold. In contrast using chemical inhibitors the accuracy was lower, predicting only 37% of compounds within two-fold of the clinical value. Poorly predicted compounds were found to either be metabolically stable and/or have high microsomal protein binding. The use of equilibrium dialysis to generate accurate protein binding measurements was especially important for highly bound drugs.

CONCLUSIONS

The current study demonstrated that the use of rhCYPs with SIMCYP® provides a robust in vitro system for predicting the likelihood and magnitude of changes in clinical exposure of compounds as a consequence of CYP3A4 inhibition by a concomitantly administered drug.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Numerous retrospective analyses have shown the utility of in vitro systems for predicting potential drug–drug interactions (DDIs).
• Prediction of DDIs from in vitro data is commonly obtained using estimates of enzyme K_i, inhibitor and substrate concentrations and absorption rate for substrate and inhibitor.

WHAT THIS STUDY ADDS

• Using a generic approach for all test compounds, the findings from the current study showed the use of recombinant P450s provide a more robust in vitro measure of P450 contribution (fraction metabolized, f_m) than that achieved when using chemical inhibitors in combination with human liver microsomes, for the prediction of potential CYP3A4 drug–drug interactions prior to clinical investigation.
• The current study supported the use of SIMCYP®, a modelling and simulation software in utilizing the in vitro measures in the prediction of potential drug–drug interactions.

     

The ABCG2 C421A polymorphism does not affect oral nitrofurantoin pharmacokinetics in healthy Chinese male subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• An increasing number of drugs on the market or under development have been identified as substrates of the ATP-binding cassette drug efflux transporter breast cancer resistance protein (BCRP; ABCG2), which can affect the pharmacokinetics of drugs by reducing absorption and/or increasing biliary elimination.
• ABCG2 C421A, a single nucleotide polymorphism associated with decreased protein expression/transport activity in vitro and higher anti-cancer drug concentrations in carriers of the C421A polymorphism, may contribute to the intersubject pharmacokinetic variability of BCRP substrates.
• Predicting the potential influence of BCRP on drug disposition or drug interactions is challenging because of the lack of a well-characterized, BCRP-selective clinical probe substrate.
• Nitrofurantoin is potentially a suitable clinical BCRP probe substrate based on preclinical and clinical information available (e.g. in vitro transport studies, Bcrp knockout mouse studies, inhibition studies in rats, and milk secretion studies in rats and humans).

WHAT THIS STUDY ADDS

• The ABCG2 C421A SNP had no effect on oral nitrofurantoin plasma and urine pharmacokinetic parameters in healthy male Chinese subjects.
• Nitrofurantoin does not appear to be a useful clinical BCRP probe.

AIMS

A number of drugs are substrates or inhibitors of the efflux transporter breast cancer resistance protein (BCRP; ABCG2), which can limit systemic exposure by reducing absorption and/or increasing biliary elimination. The identification of a BCRP-selective clinical probe drug would provide a useful tool to understand the effect of genetic polymorphisms and transporter-based drug interactions on drug pharmacokinetics. The aim of this study was to assess the utility of nitrofurantoin as a clinical probe substrate for BCRP activity by evaluating the impact of genetic variation on nitrofurantoin pharmacokinetics.

METHODS

Nitrofurantoin pharmacokinetics were studied in an open-label, single-oral dose (100 mg) study in 36 male Chinese subjects who were pre-screened for ABCG2 421 CC, CA and AA genotypes (n = 12 each). Plasma and urine concentrations of nitrofurantoin were determined by LC/MS/MS and LC/UV respectively. anova was used to compare pharmacokinetic parameters among genotypes.

RESULTS

There were no significant differences in nitrofurantoin pharmacokinetics among the genotypic cohorts. The geometric mean nitrofurantoin plasma AUC_(0-∞) (95% confidence interval) values were 2.21 (2.00, 2.45), 2.42 (2.11, 2.78) and 2.32 (1.99, 2.70) µg h ml⁻¹ and half-life values were 0.79 (0.59, 1.0), 0.76 (0.64, 0.89) and 0.72 (0.62, 0.84) h for ABCG2 421 genotypes CC, CA and AA, respectively. The percentage of dose excreted unchanged in the urine was 43, 44 and 39%, respectively.

CONCLUSIONS

The ABCG2 C421A polymorphism had no effect on nitrofurantoin plasma and urine pharmacokinetic parameters in healthy Chinese subjects. These results indicate that nitrofurantoin is not a suitable clinical probe substrate for assessing BCRP activity.     

Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers

AIMS

Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug.

METHODS

This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h).

RESULTS

Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration–time curve (AUC_τ) and maximum concentration (C_max), with changes of −55% [90% confidence interval (CI) −62, −45] and −36% (90% CI −49, −21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUC_τ (−7%; 90% CI −23, 13) and increased C_max (23%; 90% CI −1, 53), while increasing efavirenz AUC_τ (17%; 90% CI 6, 29) and not changing C_max when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz.

CONCLUSIONS

When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered.
• Furthermore, voriconazole increases the systemic exposure of efavirenz.
• Co-administration was therefore initially contraindicated.

WHAT THIS STUDY ADDS

• The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety.
• Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication.

     

Clindamycin and taste disorders

What is already known about this subject.

• The antibiotic clindamycin has a bitter taste when it is used orally.

What this study adds

• A case series on oral as well as i.v. use of clindamycin associated with taste disorders is presented.
• After corrections in a case-by-case analysis for several possible confounders such as indication, clindamycin is disproportionally associated with taste disorders.
• Serum and hence saliva and sputum clindamycin levels seem to be responsible for this reversible adverse drug reaction.

Aims

Topical use of clindamycin has been associated with taste disorders in the literature, but little is known about the nature of this adverse drug reaction. The aim of this article was to describe reports of clindamycin-induced taste disorders and to analyse the factors involved.

Methods

The adverse drug reaction database of the Netherlands Pharmacovigilance Centre was searched for reports concerning taste disorders with antibiotics. Clinical review of the cases and statistical analysis with logistic regression were performed. Characteristics of patients who reported taste disorders were compared for age, gender and formulation in clindamycin vs. other antibiotic users.

Results

Taste disorders were reported in seven (18%) of the clindamycin cases. In five reports an oral formulation was involved, in one report intravenous (i.v.) administration and in one report both formulations were used. Latency was <1 day after start and in one case taste disorders were present repeatedly at 10 min after every i.v. application. The adjusted reporting odds ratio was 7.0 (95% confidence interval 2.8, 17.3) and supports a possible causal relationship.

Conclusions

The association of clindamycin and taste disorders is supported by disproportionality analysis and seems to be independent of possible confounders such as age, gender and infections. The case reports suggest a role for clindamycin concentrations excreted in body fluids like saliva.     

Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects

AIMS

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics.

METHODS

In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22–44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. ×6 days) in the other period.

RESULTS

The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC_0–∞ and C_max were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively.

CONCLUSION

Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• No data are available on the potential drug interaction of sitagliptin and glyburide.
• Sitagliptin belongs to a new class of drugs called DPP-4 inhibitors recently approved for the treatment of Type 2 diabetes.

WHAT THIS STUDY ADDS

• Glyburide is a commonly used sulphonylurea medication to treat Type 2 diabetes.
• Combination therapy is often required to achieve adequate glucose control in Type 2 diabetes.
• Sitagliptin does not appear to interfere with glyburide pharmacokinetics and therefore may be potentially co-administered with glyburide for the treatment of Type 2 diabetes.

     

Evidence of the in vivo esterification of budesonide in human airways

AIMS

Budesonide, unlike fluticasone propionate, undergoes fatty acid esterification in the lungs, and there is a need to characterize fully the distribution and fate of the two drugs after inhalation in humans.

METHODS

This open-label, randomized study was performed in adults undergoing whole lung or lobar resection resulting from lung cancer. Patients were given single 1000-μg doses of both budesonide and fluticasone propionate via dry powder inhalers before surgery. Tissue samples from peripheral and central lung, an ex vivo bronchial brush sample and intercostal muscle, together with plasma samples, were taken during surgery and analysed by liquid chromatography plus tandem mass spectrometry.

RESULTS

Lung tissue samples were obtained from 22 patients at surgery, 1–43 h after drug dosing. Budesonide was detectable from earliest sampling in central and peripheral lung tissue up to 10 h (in six of 22 samples), fluticasone propionate up to 22 h after inhalation (in 16 of 22 samples), and budesonide oleate up to 43 h after inhalation (in 21 of 22 samples). Budesonide, but not fluticasone propionate, was detected in intercostal muscle for up to 10 h after inhalation. Bronchial brush samples showed the presence of fluticasone propionate for up to 18 h, suggesting the presence of undissolved drug powder particles in the airway lumen.

CONCLUSION

Sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and suitability for once-daily administration.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• In vitro studies with human bronchial epithelial cells have shown that budesonide undergoes rapid, extensive and reversible intracellular esterification, a finding that is believed to contribute to retention and prolonged duration of action.
• A case report has suggested retention of budesonide in the lungs of patients undergoing surgical resection.
• This study evaluated, for the first time, the esterification (and distribution) of inhaled budesonide and fluticasone propionate in vivo in human lung.

WHAT THIS STUDY ADDS

• This study has unequivocally shown that budesonide undergoes esterification in human lungs in vivo.
• Budesonide was detectable in central and peripheral lung tissue for 10 h, and budesonide oleate up to 43 h after inhalation.
• The sustained retention of budesonide esters in the lungs probably contributes to the prolonged duration of action and once-daily efficacy of budesonide.

     

Does a physician's specialty influence the recording of medication history in patients' case notes?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Physicians undertake the documentation of medication history during clerking; where all the necessary information that guides the diagnostic and patient management tasks are obtained.
• Medication histories documented by physicians are often incomplete and generally sketchy; however, the impact of a physician''s specialty on the frequency and depth of medication history they document has not been studied.

WHAT THIS STUDY ADDS

• The depth and frequency of medication history documented by physicians is significantly influenced by their specialties.
• Physicians appear more interested in documenting more frequently and in greater depth medication history information that appears to aid diagnostic tasks in their specific specialty.

AIMS

To determine the impact of a physician''s specialty on the frequency and depth of medication history documented in patient medical records.

METHODS

A cross-sectional assessment of the frequency and depth of medication history information documented by 123 physicians for 900 randomly selected patients stratified across Cardiology, Chest, Dermatology, Endocrine, Gastroenterology, Haematology, Neurology, Psychiatry and Renal specialties was carried out at a 900-bed teaching hospital located in Ibadan, Nigeria.

RESULTS

Four hundred and forty-three (49.2%) of the cohort were males and 457 (50.8%) were females; with mean ages 43.2 ± 18.6 and 43.1 ± 17.9 years respectively. Physicians'' specialties significantly influenced the depth of documentation of the medication history information across the nine specialties (P < 0.0001). Post hoc pair-wise comparisons with Tukey''s HSD test showed that the mean scores for adverse drug reactions and adherence to medicines was highest in the Cardiology specialty; while the Chest specialty had the highest mean scores for allergy to drugs, food, chemicals and cigarette smoking. Mean scores for the use of alcohol; illicit drugs; dietary restrictions was highest for Gastroenterology, Psychiatry and Endocrine specialties respectively. Physicians'' specialties also significantly influenced the frequency of documentation of the medication history across the nine specialties (P < 0.0001).

CONCLUSIONS

Physicians appear to document more frequently and in greater depth medication history information that may aid the diagnostic tasks in their specific specialty. Researchers and other users of medication history data documented in patients'' medical records by physicians may want to take special cognizance of this phenomenon.     

Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants

AIMS

To investigate time-dependent inhibition (TDI) of human drug metabolizing CYP enzymes by tricyclic antidepressants (TCAs).

METHODS

CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A/CYP3A4 activities were investigated following co- and preincubation with TCAs using human liver microsomes (HLM) and human recombinant CYP proteins (expressed in Escherichia coli) as the enzyme sources. A two-step incubation method was employed to examine the in vitro mechanism-based inactivation (MBI) criteria. Potential metabolite–intermediate complex (MIC) formation was studied by spectral analysis.

RESULTS

TCAs generally exhibited significant TDI of recombinant CYP1A2, CYP2C19 and CYP2D6 (>10% positive inhibition differences between co- and preincubation conditions). TDI of recombinant CYP2C9 was minor (<10%), and was minor or absent in experiments utilizing recombinant CYP3A4 or HLM as the enzyme sources. Where observed, TDI of recombinant CYP occurred via alkylamine MIC formation, but evidence to support similar behaviour in HLM was limited. Indeed, only secondary amine TCAs reduced the apparent P450 content of HLM (3–6%) consistent with complexation. As a representative TCA, nortriptyline fulfilled the in vitro MBI criteria using recombinant CYP2C19 and CYP3A4 (K_I and k_inact values of 4 µm and 0.19 min⁻¹, and 70 µm and 0.06 min⁻¹), but not with the human liver microsomal enzymes.

CONCLUSIONS

TCAs appear to have minimal potential for MBI of human liver microsomal CYP enzymes involved in drug metabolism. HLM and recombinant CYP (expressed in E. coli) are not equivalent enzyme sources for evaluating the TDI associated with some drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Much of the literature evidence for mechanism-based inactivation (MBI) of CYP by tricyclic antidepressants is limited to studies in rat liver microsomes.
• One report from this laboratory characterized MBI of human recombinant CYP2C8 by nortriptyline.

WHAT THIS STUDY ADDS

• Tricyclic antidepressants form alkylamine metabolite-intermediate complexes with human recombinant CYP enzymes (expressed in Escherichia coli) relatively easily, resulting in time-dependent inhibition.
• Evidence to support similar irreversible inhibition using human liver microsomal (HLM) fractions is limited.
• HLM and recombinant CYP (expressed in E. coli) are not equivalent enzyme sources for evaluating the time-dependent inhibition of human drug metabolizing CYP that is associated with some drugs.

     

Knowledge creation about ADRs – turning the perspective from the rear mirror to the projector?

Aims

Spontaneous reports of adverse drug reactions (ADRs) are often the only documentation used to justify the recall of drugs from the market. The purpose of this study was to investigate whether it would have been possible to foresee serious ADR cases based on available information on ADRs reported in Phase II and III clinical trials before marketing.

Methods

We conducted a retrospective analysis of reported ADR data in Phase II/III clinical trials in the registration material for three different ADR scenarios: (i) trovafloxacin/alatrofloxacin and hepatotoxicity; (ii) tolcapone and hepatotoxicity and neuroleptic malignant syndrome; and (iii) rituximab and cytokine release syndrome. We chose the scenarios because they were of serious character and caused great damage to the patients and because of different outcomes of the scientific discussions in the regulatory agencies.

Results

In all three cases, the registration material contained observations of ADRs, but there had been no follow-up on these observations. ADRs were mentioned in the summary of product information (SPC) purely as information, to some extent accompanied by recommendations. The information was not converted into new knowledge and remained tacit knowledge embedded in the SPCs disseminated to health professionals/prescribers.

Conclusions

The registration material analysed contained information about ADRs that were reported later, meaning that it would have been possible to foresee the occurrence of the ADRs at the time of licensing. More active utilization of the information from Phase II/III clinical trials is recommended to prevent the appearance of unexpected ADRs and further emphasis in SPC warnings to doctors about possible serious ADRs.

What is already known about this subject?

• Serious and unexpected adverse drug reactions (ADRs) have been reported shortly after marketing of a number of drugs.
• Review of ADR cases by the regulatory authorities has resulted in suspension of drugs or restrictions in product information.

What this study adds?

• Information about serious and unexpected ADRs of three drugs with reported serious ADRs was already present in the registration files.
• Observations of these ADRs were not investigated further before marketing.
• A more active utilization of the ADR information in premarketing studies could probably prevent the appearance of unexpected and serious ADR cases after marketing.

     

Is a positive history of non-anaesthetic drug allergy a predictive factor for positive allergy tests to anaesthetics?

AIMS

International recommendations stipulate not performing screening skin tests to a drug in the absence of a clinical history consistent with that specific drug allergy. Nevertheless, two publications showed that a positive history of non-anaesthetic drug allergy was the only predictive factor for a positive skin test when screening for allergy to anaesthetic drugs was done. We selected from a surgical population 40 volunteers with a prior history of allergy to non-anaesthetic drugs in order to analyse the prevalence of positive allergy tests to anaesthetics.

METHODS

The selected adult patients were tested for 11 anaesthetic drugs using in vivo tests: skin prick (SPT) and intradermal (IDT) tests and in vitro tests: the basophil activation test (BAT) and detection of drug-specific immunoglobulin E (IgE).

RESULTS

The prevalence for the positive SPT and IDT was 1.6% and 5.8% respectively. The result of flow cytometry agreed with the SPT in five out of seven positive SPT (71%). IgEs confirmed two positive SPT with corresponding positive BAT. Ten per cent of the patients had a positive prick test to neuromuscular blocking agents (NMBA). For midazolam none of the SPT was positive, but 11 patients had positive IDT nonconfirmed by BAT.

CONCLUSION

The prevalence of positive in vivo and in vitro allergy tests to NMBAs is higher in our study population. This could be an argument for pre-operative SPT to NMBAs for the surgical population with reported non-anaesthetic drug allergies. A larger prospective study is needed to validate changes in clinical practice.