Paediatric Drug Development and Formulation Design-a European Perspective.

The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize "better" medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the "Guideline on the Pharmaceutical Development of Medicines for Paediatric Use." Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.

Safe and effective pharmacotherapy in infants and preschool children: importance of formulation aspects.

Safe and effective paediatric pharmacotherapy requires careful evaluation of the type of drug substance, the necessary dose and the age-appropriateness of the formulation. Generally, the younger the child, the more the attention that is required. For decades, there has been a general lack of (authorised) formulations that children are able to and willing to take. Moreover, little was known on the impact of pharmaceutical aspects on the age-appropriateness of a paediatric medicine. As a result of legislative incentives, such knowledge is increasingly becoming available. It has become evident that rapidly dissolving tablets with a diameter of 2 mm (mini-tablets) can be used in preterm neonates and non-rapidly dissolving 2 mm mini-tablets in infants from 6 months of age. In addition, uncoated 4 mm mini-tablets can be used in infants from the age of 1 year. Also, there is some evidence that children prefer mini-tablets over a powder, suspension or syrup. Other novel types of age-appropriate oral formulations such as orodispersible films may further add to the treatment possibilities. This review provides an overview of the current knowledge on oral formulations for infants and preschool children, the advantages and disadvantages of the different types of dosage forms and the age groups by which these can likely be used.

Methods of administering oral formulations and child acceptability.

INTRODUCTION: Children may be unable or unwilling to swallow medicines. In order to avoid or accommodate any such problems, parents may decide to administer medicines other than intended. The aim of this study was to investigate how parents administered four oral placebo formulations to infants and preschool children and how the applied methods correlated with child acceptability. METHODS: Parents were asked to administer a 4 mm mini-tablet, powder, suspension and syrup to their child twice on one day and to report the child characteristics and administration details in a participant diary. RESULTS: A 151 children were included. The tablet, syrup and suspension were mostly given on their own, whereas the powder was commonly given with food or drink. Generally, the higher the child acceptability (VAS-score) of the first administration of a specific formulation, the less frequently its method of administration was changed. A change in the method of administration of the same formulation involving (a larger quantity of) food or drink generally resulted in a higher VAS-score. CONCLUSIONS: The joint administration of medicines with food or drink is an effective strategy to ensure swallowing. This study supports earlier findings that 4mm mini-tablets are a suitable dosage form from infant age.

Oral medicines for children in the European paediatric investigation plans.

INTRODUCTION: Pharmaceutical industry is no longer allowed to develop new medicines for use in adults only, as the 2007 Paediatric Regulation requires children to be considered also. The plans for such paediatric development called Paediatric Investigation Plans (PIPs) are subject to agreement by the European Medicines Agency (EMA) and its Paediatric Committee (PDCO). The aim of this study was to evaluate the key characteristics of oral paediatric medicines in the PIPs and the changes implemented as a result of the EMA/PDCO review. METHODS: All PIPs agreed by 31 December 2011 were identified through a proprietary EMA-database. PIPs were included if they contained an agreed proposal to develop an oral medicine for children 0 to 11 years. Information on the therapeutic area (EMA classification system); target age range (as defined by industry) and pharmaceutical characteristics (active substance, dosage form(s) as listed in the PIP, strength of each dosage form, excipients in each strength of each dosage form) was extracted from the EMA website or the EMA/PDCO assessment reports. RESULTS: A hundred and fifty PIPs were included corresponding to 16 therapeutic areas and 220 oral dosage forms in 431 strengths/compositions. Eighty-two PIPs (37%) included tablets, 44 (20%) liquids and 35 (16%) dosage forms with a specific composition/strength that were stored as a solid but swallowed as a liquid e.g. dispersible tablets. The EMA/PDCO review resulted in an increase of 13 (207 to 220) oral paediatric dosage forms and 44 (387 to 431) dosage forms with a specific composition/strength. For many PIPs, the target age range was widened and the excipient composition and usability aspects modified. CONCLUSION: The EMA/PDCO review realized an increase in the number of requirements for the development of oral dosage forms and a larger increase in the number of dosage forms with a specific composition/strength, both targeting younger children. Changes to their pharmaceutical design were less profound.

Perioperative substitution of anti-epileptic drugs.

A common problem in brain and abdominal surgery is the perioperative substitution of antiepileptic drugs (AEDs) when patients are temporarily unable to take these drugs orally. We searched the literature for clinical trials with patients or healthy volunteers in whom non-oral formulations of AEDs as substitution were tested. Different search engines, handbooks, expert opinion and our own experience, were used. Pharmaceutical companies were approached for recommendations. This led to three categories of replacement: 1. commercial alternative (n = 10) for clonazepam, diazepam, lacosamide, levetiracetam, lorazepam, midazolam, nitrazepam, phenobarbital, phenytoin, and valproic acid; 2. alternatives that must be prepared (n = 6) for carbamazepine, clobazam, lamotrigine, oxcarbazepine, primidone, topiramate; 3. no alternative (n = 7) for ethosuccimide, felbamate, retigabine, stiripentol, tiagabine, vigabatrin, zonisamide. Thus, for a substantial number of AEDs, unofficial perioperative treatment strategies need to be followed for lack of alternatives to oral administration. There is little clinical research addressing the equivalence of oral and parenteral formulas. Perioperative substitution of AEDs is an underestimated problem, and may increase the risk of postoperative seizures.

Acceptability of different oral formulations in infants and preschool children.

OBJECTIVE: Liquid medicines are easy to swallow. However, they may have disadvantages, such as a bad taste or refrigerated storage conditions. These disadvantages may be avoided by the use of oral solid medicines, such as powders or tablets. The aim of this study was to investigate the acceptability of and preference among four oral formulations in domiciliary infants and preschool children in The Netherlands. METHODS: Parents administered four oral placebo dosage forms that were aimed at a neutral taste, at home, to their child (1-4 years of age) twice on one day following a randomised cross-over design: small (4 mm) tablet, powder, suspension and syrup. They were asked to report the child's acceptability by a score on a 10 cm visual analogue scale (VAS score) and by the result of the intake. At the end of the study, they were asked to report the preference of the child and themselves. RESULTS: 183 children were included and 148 children were evaluated. The data revealed a period/cross-over effect. The estimate of the mean VAS score was significantly higher for the tablet than for the suspension (tablet 9.39/9.01; powder 8.84/8.20, suspension 8.26/7.90, syrup 8.35/8.19; data day 1/all days). The estimate of the mean number of intakes fully swallowed was significantly higher for the tablet than for the other formulations (all p values <0.05). Children and parents preferred the tablet and syrup over the suspension and the suspension over the powder (all p values <0.05). CONCLUSIONS: All formulations were well accepted. The tablets were the best accepted formulation; the tablets and syrup the most preferred. TRIAL REGISTRATION NUMBER: ISRCTN63138435.

Genetic variation and the risk of haloperidol-related parkinsonism in elderly patients: a candidate gene approach.

Factors that influence the variation in occurrence of antipsychotic-related parkinsonism in elderly have not been well elucidated. The aim of this study was to investigate whether previous identified and studied genetic polymorphisms at DRD2, ANKK1, DRD3, HTR2A, HTR2C, RGS2, COMT, and BDNF genes are associated with antipsychotic-related parkinsonism in elderly patients.This cross-sectional study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. The investigated predictors were polymorphisms in DRD2 (141CIns/Del and C957T), ANNK1 (TaqIA), DRD3 (Ser9Gly), HTR2A (-1438G>A and His452Tyr), HTR2C (Cys23Ser and -759C/T), RGS2 (+2971C>G), COMT (G158A), and BDNF (Val66Met). Frequencies of the -759 T allele of the HTR2C gene and the 158A allele of the COMT gene were significantly higher in patients without antipsychotic-induced parkinsonism (AIP) (nominal P = 0.03 and P = 0.02, respectively). -759 T allele carriership in females was associated with a lower risk of AIP (adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.85). The decrease in risk of AIP in carriers of the COMT 158A allele did not reach statistical significance. No significant associations were found between AIP and the remaining selected polymorphisms.Although validation is needed, this study suggests that carriership of the -759 T allele of the HTR2C gene in females may be protective against development of parkinsonism in elderly patients during treatment with haloperidol.

Parkinsonism in elderly users of haloperidol: associated with dose, plasma concentration, and duration of use.

Factors that influence the variation in occurrence of antipsychotic-induced parkinsonism (AIP) in the elderly have not been well elucidated. The aim of this study was to investigate the association between parkinsonism in elderly users of haloperidol and prescribed dose, plasma concentration, and duration of use of haloperidol in a cross-sectional design. This study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. Prescribed haloperidol dose varied from 0.3 to 5 mg/d. Plasma concentration ranged from 0.13 to 4.11 µg/L, with one outlying measurement (21.43 µg/L). Dose is moderate but significantly associated with haloperidol plasma concentration (weighted R2 = 0.32; P < 0.001). Variability in the total score on the Simpson Angus Scale could not be explained by the variability in dose, concentration (respectively R2 = 0.003 and 0.001) nor duration of use of haloperidol. Smoking showed to be not significantly protective in the development of AIP (crude odds ratio, 0.39; 95% confidence interval, 0.15-0.997; and adjusted odds ratio, 0.44; 95% confidence interval, 0.17-1.17). In a clinical practice-setting dose, neither plasma concentration nor duration of use of haloperidol is associated with an increased occurrence of AIP. This study does not support the hypothesis of the peripheral pharmacokinetic explanation for the high prevalence of AIP and differences in AIP sensitivity in the elderly during treatment with haloperidol.

Quality of life of elderly patients with antipsychotic-induced parkinsonism: a cross-sectional study.

OBJECTIVES: Antipsychotic-induced parkinsonism (AIP) is one of the most common adverse effects of haloperidol. The purpose of this study was to investigate the association between AIP and quality of life of elderly patients treated with haloperidol. DESIGN: Cross-sectional study design. SETTING: Eleven nursing homes, geriatric departments of 2 hospitals, and 3 mental health care centers in the Netherlands. PARTICIPANTS: Participants were 140 elderly patients aged 65 years and older treated for at least 5 days with haloperidol. MEASUREMENTS: The presence of AIP was determined with the Simpson Angus Scale. Quality of life was scored with the QUALIDEM scale. Multivariate linear regression analysis was used to assess whether the presence of AIP and quality of life were correlated. The data of patients with advanced dementia were analyzed separately. RESULTS: Of the 140 included patients, 65 (46%) were diagnosed with AIP. Patients with AIP scored lower than patients without AIP on the QUALIDEM subscales "positive affect," "negative affect," "social relations," "social isolation," and "having something to do." In patients with advanced dementia, quality of life was not significantly different in patients with or without AIP. CONCLUSION: The presence of AIP is negatively associated with the quality of life of elderly patients treated with haloperidol.

The availability and age-appropriateness of medicines authorized for children in The Netherlands.

AIM: To study the number of medicines and active chemical entities that are authorized and commercially available for children in the Netherlands and to evaluate the age-appropriateness of the available paediatric medicines. METHODS: The availability of paediatric medicines and active chemical entities was studied with the help of a Dutch medicines database and the Summary of Product Characteristics. Medicines were categorized with respect to their route of administration, type of oral dosage form and therapeutic category. The age-appropriateness was assessed on three aspects: dose capability, suitability of the dosage form and inclusion of potentially harmful excipients. RESULTS: Three thousand five hundred and forty-two paediatric medicines containing 703 different active chemical entities were identified. This equalled half of all the medicines and chemical entities available for human use. The percentage of paediatric medicines increased with age and varied for the route of administration from 22% (dermal) to 81% (inhalation) and for the therapeutic category from 11% (uro-genital, sex hormones) to 89% (anti-parasites). The appropriateness of the paediatric medicines with respect to their authorization status, dose capability and dosage form increased with age from 27-88%. Fifty-two percent of all oral paediatric liquid formulations contained a potentially harmful excipient. CONCLUSION: This study confirms the limited availability of paediatric medicines for a broad range of therapeutic areas and shows that paediatric medicines may not be age-appropriate, even if authorized. While confirming the need for a legislative incentive, the results also provide baseline information for an estimation of the effect of the European Paediatric Regulation in the near future.

Effects of the pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes: a systematic literature review.

BACKGROUND: In view of the high rates of off-label and unlicensed prescribing of drugs in children, the US Food and Drug Administration and the European Union have implemented legislative regulations for the pharmaceutical industry to increase the number of drugs with approved pediatric labeling. However, the extent to which the effects of pharmaceutical technologic aspects of pediatric oral drugs (eg, taste, route and frequency of administration, user instructions) on patient-related outcomes (eg, efficacy, tolerability, preference, adherence) can be based on clinical evidence from the available literature is unknown. OBJECTIVE: This systematic literature review aimed to identify the nature, volume, and quality of comparative studies that have assessed the effects of pharmaceutical technologic aspects of oral pediatric drugs on patient-related outcomes. METHODS: The Cochrane, EMBASE, and MEDLINE databases were searched from their start through December 31, 2009. Studies were eligible for inclusion if they were published in English; included search terms for child, study design, medicine, formulation aspects, dosage form, routes of administration, patient acceptance, adherence, side effects and tolerability, and/or efficacy; reported on > or = 10 children aged 0 to <18 years; and described the effects of > or = 1 of 3 pharmaceutical technologic aspects of an oral pediatric drug (formulation and dosage form; route and frequency of administration; and/or packaging, administration device, and user instruction) on > or = 1 of 6 patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and/or adherence). Studies were excluded if they concerned a nonallopathic drug (ie, homeopathic remedy, anthroposophic drug, herbal supplement, or food supplement); related to asthma (because modern asthma treatment protocols strongly favor the use of drug inhalation above oral medication); and/or related to analgesics. The characteristics of each of the included publications were assessed with respect to pharmaceutical technologic aspect studied; patient-related outcomes studied; pharmacotherapeutic indication; year of publication; geographic location; number and age of the included subjects; and sponsorship by industry and/or author affiliation with the pharmaceutical industry. The electronic search was supplemented with a manual search of the cited references. RESULTS: Ninety-four publications were identified as eligible for inclusion. These publications reported on 176 assessments of the effects of > or = 1 pharmaceutical technologic aspect on > or = 1 patient-related outcome. Fifty-five percent of the studies were conducted in children aged 2 or 3 years, and 69% in children aged 4 or 5 years. Forty-three percent of the publications included > or = 100 patients. Fifty-one percent of the studies were conducted in the United States or Canada, and 29% in Europe. Antibacterials for systemic use were the subject of 30% of the included publications. Two of the 94 publications were of appropriate methodologic quality (Jadad score > or = 4). Forty-nine percent of the studies were sponsored by the pharmaceutical industry or were written by > or = 1 author affiliated with the industry. Sixty-eight percent of the included studies had Jadad scores of 0 or 1 (poor quality). The proportion of industry-sponsored or industry-authored studies with a Jadad score > or = 2 or in > or = 100 children was not significantly different from that of non-industry-sponsored or-authored studies. The proportion of industry-sponsored or industry-authored studies conducted in the United States/Canada (48 [51%]) was not significantly different from that of studies conducted elsewhere (46 [49%]). The distribution of technologic aspects assessed in the included studies were formulation and dosage form, 48%; route and frequency of administration, 44%; and packaging, administration device, and user instruction, 8%. Seventy-six assessments included > or = 100 patients. Twenty-one of these assessments addressed patient acceptance or patient preference; 17, clinical efficacy; and 14, side effects and tolerability. CONCLUSIONS: This systematic review identified 94 articles on oral drugs for use in children and adolescents, which reported on a total 176 assessments of the effects of 3 pharmaceutical technologic aspects (formulation and dosage form; route and frequency of administration; and packaging, administration device, and user instruction) on 6 patient-related outcomes (clinical efficacy, side effects and tolerability, patient preference, patient acceptance, administration errors, and adherence). Only 2 of the 94 publications were of appropriate methodologic quality. These results suggest that published clinical evidence to support pharmaceutical development programs is limited.

Effect of cytochrome P450 2D6 genotype on maternal paroxetine plasma concentrations during pregnancy.

BACKGROUND AND OBJECTIVE: Increasing numbers of women in childbearing years are treated with antidepressants. Concerns regarding fetal exposure to medication has led to large studies on drug effects on birth outcome and on the risk of congenital anomalies. The risk of adverse effects due to paroxetine use during pregnancy has been associated with the extent of exposure. Nevertheless, few studies have covered dosing aspects in order to minimize fetal antidepressant exposure while limiting the risk of treatment failure. Essential pharmacokinetic data in pregnancy are lacking, even regarding paroxetine, one of the most commonly used antidepressants. We examined the changes of maternal paroxetine concentrations during pregnancy in relation to cytochrome P450 (CYP) 2D6 genotype. METHOD: An observational cohort study was conducted in 74 pregnant women aged from 25 to 45 years treated with paroxetine during pregnancy. Blood samples and information on dosing, weight, smoking and mood were provided at 16-20, 27-31 and 36-40 weeks of pregnancy. Samples were analysed for paroxetine plasma concentrations and CYP2D6 genotype. RESULTS: Women who were genotyped as extensive metabolizers (EMs) or ultra-rapid metabolizers (UMs) for CYP2D6 (EM n = 43; UM n = 1) showed steadily decreasing plasma paroxetine concentrations during the course of pregnancy, with a decrease of 0.3 microg/L (95% CI -0.58, -0.07) for each week of pregnancy. In contrast, plasma paroxetine concentrations of intermediate metabolizers (IMs [n = 25]) and poor metabolizers (PMs [n = 5]) increased during pregnancy, resulting in an increase of 0.82 microg/L (95% CI 0.42, 1.22) for each week of pregnancy. Weight gain, maternal age or smoking did not influence plasma drug concentrations. Decreasing plasma concentrations in EMs are in accordance with induced CYP2D6 activity during pregnancy. Accumulation of paroxetine in women with impaired CYP2D6 metabolism may be explained by competition with an endogenous substrate. In EMs/UMs the depressive symptoms increased significantly during the course of pregnancy, while in the IM/PM group these did not change. CONCLUSIONS: Differences in CYP2D6 genotype may have divergent effects on maternal plasma paroxetine concentrations during pregnancy, with therapeutic consequences. Accumulation of paroxetine in a considerable group of pregnant women will lead to unintended increased exposure of paroxetine to the unborn child. Knowledge about a patient's CYP2D6 genotype is indispensable when prescribing paroxetine in pregnancy [trialregister.nl Identifier ISRCTN25383361].

Compliance with platelet count monitoring recommendations and management of possible heparin-induced thrombocytopenia in hospitalized patients receiving low-molecular-weight heparin.

BACKGROUND: Summaries of product characteristics (SPCs) and clinical guideline recommendations are available for monitoring the platelet count for heparin-induced thrombocytopenia (HIT) in patients receiving low-molecular-weight heparin (LMWH). Testing for the presence of heparin-platelet factor 4 antibodies (HPF4-Ab) and starting alternative anticoagulation is recommended when HIT is suspected. OBJECTIVE: To investigate the frequency of compliance with recommendations for platelet count monitoring and management of possible HIT in hospitalized patients receiving prophylaxis and treatment dosing of LMWH for at least 5 consecutive days. METHODS: A retrospective cohort study within the Utrecht Patient Oriented Database (UPOD) was conducted. For all inpatients, all episodes of exposure to dalteparin or nadroparin for at least 5 consecutive days in 2004-2005 were selected. In 4 different nonexclusive groups of patients (all pts. receiving dalteparin, all pts. receiving nadroparin, surgical pts. with a prophylactic dose of either dalteparin or nadroparin, and pts. exposed to unfractionated heparin [UFH] within 100 days before receiving either dalteparin or nadroparin), compliance with recommendations for platelet count monitoring from SPCs and a clinical guideline was studied. The frequency of compliance with these recommendations was determined. In addition, it was determined whether patient and treatment characteristics were associated with regular platelet count monitoring. Finally, the frequency of testing for HPF4-Ab and the initiation of danaparoid treatment in patients with a drop of at least 50% in platelet count were investigated. RESULTS: A total of 6804 patients, with 7770 episodes of LMWH treatment, were included in the analysis. The frequency of compliance with platelet count monitoring recommendations was 26.3% for all patients receiving dalteparin, 35.6% for all patients receiving nadroparin, 23.0% for surgical patients receiving prophylactic dosing of either dalteparin or nadroparin, and 41.5% for patients exposed to UFH within 100 days before the start of either dalteparin or nadroparin treatment. Regular platelet count monitoring was strongly positively associated with medical patients (relative risk [RR] 2.33), surgical patients (RR 2.03), critically ill patients (RR 2.80), and those with recent exposure to UFH (RR 2.19). The frequency of testing for HPF4-Ab was 5.4% and the initiation of alternative anticoagulation with danaparoid in patients with a 50% drop in platelet count was 0%. CONCLUSIONS: The results suggest that compliance with recommendations for platelet count monitoring and management of possible HIT is low at our institution. Policies and tools to improve compliance with recommended laboratory monitoring should be developed to secure the safe use of LMWH and other medications.

Platelet measurements versus discharge diagnoses for identification of patients with potential drug-induced thrombocytopenia: a cross-sectional study in the Netherlands.

BACKGROUND: In pharmacoepidemiological studies on the risk of drug-induced blood dyscrasias, including drug-induced thrombocytopenia (DIT), hospital discharge diagnoses have been used to identify potential cases. One of the possible limitations of discharge diagnoses is that due to incomplete registration not all potential cases are identified, which may limit statistical power. Clinical laboratory data have been suggested as a data type that is potentially more sensitive for identifying potential cases of adverse drug reactions than discharge diagnoses. OBJECTIVE: To compare the number of patients with potential DIT that could be identified by using platelet measurements with the number of patients with potential DIT that could be identified by using discharge diagnoses for thrombocytopenia within a population of hospitalized patients. METHODS: The study population of this cross-sectional study comprised all patients admitted to the University Medical Center Utrecht in 2004 and 2005, as captured within the Utrecht Patient Oriented Database (UPOD). The ratio of the number of patients with potential DIT based on platelet measurements (>or=1 platelet count below 100x10(9)/L without alternative diagnoses for DIT) to the number of patients with potential DIT based on discharge diagnoses for thrombocytopenia (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] codes 287.3-287.5 without alternative diagnoses for DIT) was determined. RESULTS: Within the study period there were 56,411 hospitalizations. 2817 patients (5.0%) had >or=1 platelet count below 100x10(9)/L. In 96.3% of these patients, alternative diagnoses for DIT were present, resulting in 103 (0.2%) patients with potential DIT based on platelet measurements. There were 74 patients (0.1%) with a discharge diagnosis for thrombocytopenia. In 81.1% of these patients, alternative diagnoses for DIT were present, resulting in 14 (0.02%) patients with potential DIT based on discharge diagnoses. This resulted in a ratio of the number of patients with potential DIT based on platelet measurements to the number of patients with potential DIT based on discharge diagnoses for thrombocytopenia of seven. CONCLUSION: This study showed that the use of platelet measurements is a more sensitive approach to the identification of patients with potential DIT than the use of discharge diagnoses for thrombocytopenia.

Validity and reliability of the Simpson-Angus Scale (SAS) in drug induced parkinsonism in the elderly.

BACKGROUND: Quantification of drug induced parkinsonism (DIP) for study purposes is difficult. The most often used Simpson Angus Scale (SAS) lacks proper clinimetric evaluation. The newer Schedule for Assessment of Drug-Induced Movement Disorders (SADIMoD) shows good clinimetric characteristics, but has not been used in published clinical studies, probably due to the complexity of the scale. OBJECTIVES: To evaluate internal consistency and inter-rater reliability of the SAS and the correlation ot f the SAS with the parkinsonism subscale of the SADIMoD in elderly. METHOD: Fifteen elderly diagnosed with DIP were recruited. The patients were assessed three times with the SAS by three independent investigators. The resident also performed the SADIMoD. Internal consistency was measured by Cronbach's alpha-coefficient, inter-rater variability was examined with weighted kappa values and percentage of agreement and correlation to SADIMoD by Spearman's correlation coefficient. RESULTS: SAS demonstrated good internal consistency reliability (Cronbach's alpha coefficients 0.83). Inter-rater reliability for sum score was good. For individual items slight agreement on the item salivation and moderate to very good agreement on remaining items calculated by weighted kappa values was reached. We found 87-100% agreement on the individual items with acceptance of 1 point difference between raters. The SAS demonstrated acceptable correlation with the SADIMoD parkinsonism subscale scores (Spearman's rho = 0.66; p < 0.01). CONCLUSION: The SAS appears to be a valid and by different instructed health care professionals easy to perform research tool to evaluate DIP.

Antipsychotic drug use and risk of pneumonia in elderly people.

OBJECTIVES: To investigate the association between antipsychotic drug use and risk of pneumonia in elderly people. DESIGN: A nested case-control analysis. SETTING: Data were used from the PHARMO database, which collates information from community pharmacies and hospital discharge records. PARTICIPANTS: A cohort of 22,944 elderly people with at least one antipsychotic prescription; 543 cases of hospital admission for pneumonia were identified. Cases were compared with four randomly selected controls matched on index date. MEASUREMENTS: Antipsychotic drug use in the year before the index date was classified as current, recent, or past use. No prescription for an antipsychotic in the year before the index date was classified as no use. The strength of the association between use of antipsychotics and the development of pneumonia was estimated using multivariate logistic regression analysis and expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Current use of antipsychotics was associated with an almost 60% increase in the risk of pneumonia (adjusted OR=1.6, 95% CI=1.3-2.1). The risk was highest during the first week after initiation of an antipsychotic (adjusted OR=4.5, 95% CI=2.8-7.3). Similar associations were found after exclusion of elderly people with a diagnosis of delirium. Current users of atypical agents showed a higher risk of pneumonia (adjusted OR=3.1, 95% CI=1.9-5.1) than users of conventional agents (adjusted OR=1.5, 95% CI=1.2-1.9). There was no clear dose-response relationship. CONCLUSION: Use of antipsychotics in elderly people is associated with greater risk of pneumonia. This risk is highest shortly after the initiation of treatment, with the greatest increase in risk found for atypical antipsychotics.

Linking laboratory and medication data: new opportunities for pharmacoepidemiological research.

Transfer of automated laboratory data collected during routine clinical care from the laboratory information system into a database format that enables linkage to other administrative (e.g., patient characteristics) or clinical (e.g., medication, diagnoses, procedures) data provides a valuable tool for clinical epidemiological research. It allows the investigation of biochemical characteristics of diseases, therapeutic effects and diagnostic and/or prognostic markers for disease with easy access and at relatively low cost. To this end, the Utrecht Patient Oriented Database (UPOD), an infrastructure of relational databases comprising data on patient characteristics, laboratory test results, medication orders, hospital discharge diagnoses and medical procedures for all patients treated at the University Medical Centre Utrecht since January 2004, was established. Current research within UPOD is focused on the innovative linkage of laboratory and medication data, which, for example, makes it possible to assess the quality of pharmacotherapy in clinical practice, to investigate interference between laboratory tests and drugs, to study the risk of adverse drug reactions, and to develop diagnostic and prognostic markers or algorithms for adverse drug reactions. Although recently established, we believe that UPOD broadens the opportunities for clinical pharmacoepidemiological research and can contribute to patient care from a laboratory perspective.

Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations.

The approach to paediatric drug dosing needs to be based on the physiological characteristics of the child and the pharmacokinetic parameters of the drug. This review summarises the current knowledge on developmental changes in absorption, distribution, metabolism and excretion and combines this knowledge with in vivo and in vitro pharmacokinetic data that are currently available. In addition, dosage adjustments based on practical problems, such as child-friendly formulations and feeding regimens, disease state, genetic make-up and environmental influences are presented. Modification of a dosage based on absorption, depends on the route of absorption, the physico chemical properties of the drug and the age of the child. For oral drug absorption, a distinction should be made between the very young and children over a few weeks old. In the latter case, it is likely that practical considerations, like appropriate formulations, have much greater relevance to oral drug absorption. The volume of distribution (V(d)) may be altered in children. Hydrophilic drugs with a high V(d) in adults should be normalised to bodyweight in young children (age <2 years), whereas hydrophilic drugs with a low V(d) in adults should be normalised to body surface area (BSA) in these children. For drugs that are metabolised by the liver, the effect of the V(d) becomes apparent in children <2 months of age. In general, only the first dose should be based on the V(d); subsequent doses should be determined by the clearance. Pharmacokinetic studies on renal and liver function clarify that a distinction should be made between maturation and growth of the organs. After the maturation process has finished, the main influences on the clearance of drugs are growth and changes in blood flow of the liver and kidney. Drugs that are primarily metabolised by the liver should be administered with extreme care until the age of 2 months. Modification of dosing should be based on response and on therapeutic drug monitoring. At the age of 2-6 months, a general guideline based on bodyweight may be used. After 6 months of age, BSA is a good marker as a basis for drug dosing. However, even at this age, drugs that are primarily metabolised by cytochrome P450 2D6 and uridine diphosphate glucuronosyltransferase should be normalised to bodyweight. In the first 2 years of life, the renal excretion rate should be determined by markers of renal function, such as serum creatinine and p-aminohippuric acid clearance. A dosage guideline for drugs that are significantly excreted by the kidney should be based on the determination of renal function in first 2 years of life. After maturation, the dose should be normalised to BSA. These guidelines are intended to be used in clinical practice and to form a basis for more research. The integration of these guidelines, and combining them with pharmacodynamic effects, should be considered and could form a basis for further study.

Drug-induced thrombocytopenia: a population study.

BACKGROUND: Drug-induced immune thrombocytopenia, excluding heparin-induced thrombocytopenia, is a rare adverse drug reaction for which the evidence about frequency, relative risk and risk factors mainly originates from case reports and case studies. This study aims to quantify the risk for thrombocytopenia following exposure to drugs that are most often reported to cause thrombocytopenia in the general population. METHODS: A retrospective, case-control study was conducted within the PHARMO record linkage system. Cases were defined as patients hospitalised for thrombocytopenia in the period 1 January 1990 to 31 December 2002. For each case, up to four controls were matched based on age, sex and geographical area. Exposure on the index date to anticonvulsants, beta-lactam antibacterials, cinchona alkaloids, disease modifying antirheumatic drugs (DMARDs), diuretics, NSAIDs, sulfonamide antibacterials and tuberculostatics was assessed and categorised into mutually exclusive groups of current, recent, past and non-use. The risk was quantified with multivariate conditional logistic regression analysis. RESULTS: The study population comprised 705 cases and 2658 controls. Current use of beta-lactam antibacterials was associated with an increased risk for thrombocytopenia (adjusted odds ratio 7.4, 95% CI 1.8, 29.6). Increased risk estimates, although not significant, were found for current exposure to DMARDs and the sulfonamide antibacterial cotrimoxazole (trimethoprim/sulfamethoxazole). No increased risk was found for anticonvulsants, cinchona alkaloids, diuretics, NSAIDs or tuberculostatics. CONCLUSION: More evidence for an increased risk for thrombocytopenia in current use of beta-lactam antibacterials in the general population was provided. The expected increase in risk could not be confirmed for the other drugs investigated, which is possibly a result of the limited statistical power. Future studies including more patients and with laboratory data should confirm our findings before drawing definite conclusions.