Objective: We have explored the advantages and disadvantages of a parallel group designs with or without washout and delayed start designs to help understand the difficulties in defining a long term (disease modifying) effect of drug... more
Objective: We have explored the advantages and disadvantages of a parallel group designs with or without washout and delayed start designs to help understand the difficulties in defining a long term (disease modifying) effect of drug treatment in slowly progressive diseases. Introduction: Parkinson’s and Alzheimer Disease are neurological diseases which progress relatively slowly (years). Ideally, treatment should slow down or even reverse the progression of the disease. The onset of the treatment effect might either be short and reversible after cessation of treatment or long and persisting after stopping treatment. Reversible short term effects are referred to as ‘symptomatic ’ while long-term effects are referred to as ‘protective ’ or ‘disease modifying ’ [1]. In order to estimate the actual treatment effect it is essential
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Padrini and Quintieri [3] raise several questions about our description of warfarin pharmacokinetics and anticoagulant effect [4]. They acknowledge that the contribution of R-warfarin to the effect produced by S-warfarin is controversial... more
Padrini and Quintieri [3] raise several questions about our description of warfarin pharmacokinetics and anticoagulant effect [4]. They acknowledge that the contribution of R-warfarin to the effect produced by S-warfarin is controversial and question our conclusion that R-warfarin appears to act as a competitive antagonist. They are also concerned that we found the plasma clearance of R-warfarin to be higher in S-warfarin slow metabolizers with cytochrome P450 CYP2C9 (CYP2C9*1/*3) genotypes. In addition, they note that our estimate of prothrombin complex (PCA) half-life is shorter than the plasma half-life of prothrombin. Finally, they contend that because the reference range of International Normalized Ratio (INR) 1.5–2.5 used to adjust warfarin dose in our study population was lower than that used in other contexts (INR 2–3), then this would lead to equivocal results. We thank Padrini and Quintieri [3] for raising these issues some of which we agree may be controversial. Like Padrini and Quintieri [3] we expected R-warfarin to have lower potency but otherwise to behave like S-warfarin and contribute to the anticoagulant effect. However, the data did not support this expectation and we found that the Rwarfarin contribution to the observed anticoagulant effect was described better by assuming it was a competitive antagonist. Our conclusions are based on a large patient population study and do not give experimental support for R-warfarin to act as an inhibitor of PCA synthesis when combined with S-warfarin. Thus, we can only contribute to the existing controversy. The effect of CYP2C9 genotype on R-warfarin clearance uses a model identical to that used to confirm the wellknown effect of CYP2C9 genotype on S-warfarin clearance. There is no mechanistic reason to believe that R-warfarin cannot be metabolized by CYP2C9 enzymes. The actual reason may be more complicated. It could be that when CYP2C9 activity is decreased there is a compensatory increase in other enzymes (e.g. CYP2C19) which could explain the increase in R-warfarin clearance. It is perhaps unexpected to find that the clearance of R-warfarin is increased but the evidence for this uses the same kind of data and the same kind of model used for S-warfarin. British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 2305–2306 2305
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Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg(-1) is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown.... more
Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg(-1) is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown. Children (n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg·kg(-1) before surgery and 20 mg·kg(-1) rectally at the end of surgery with diclofenac suspension 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first-order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout. Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect (EMAX ) was 4.9. The concentration resulting in 50% of EMAX (C50 ) was 1.23 mg·l(-1) for diclofenac and 13.3 mg·l(-1) for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg·kg(-1) with acetaminophen 15 mg·kg(-1) achieves equivalent analgesia to acetaminophen 30 mg·kg(-1) . Combination therapy can be used to achieve similar analgesia with lower doses of both drugs.
Research Interests: Pharmacokinetics, Drug interactions, Treatment Outcome, Medicine, Humans, and 15 moreChild, Paediatric Anaesthesia, Female, Male, Infant, Pharmacodynamics, Pediatric Anaesthesia, Diclofenac, Combination drug therapy, Acetaminophen, Tonsillectomy, Pediatric Anesthesia, Pain Measurement, Child preschool, and Paediatrics and reproductive medicine
Modeling and simulation in general, and specifically clinical trial simulation (CTS), have been recognized by the (larger) pharmaceutical companies and regulatory authorities as being pivotal to improving the efficiency of the drug... more
Modeling and simulation in general, and specifically clinical trial simulation (CTS), have been recognized by the (larger) pharmaceutical companies and regulatory authorities as being pivotal to improving the efficiency of the drug development process. This includes the use of CTS to learn about drug effectiveness and safety and to optimize trial designs at the various stages of development. By reviewing papers published during the period January 2000-January 2010, this paper discusses recent developments with respect to methodology, applications, and lessons learned in the use of CTS in the development and clinical use of specific drugs. It is expected that future CTS experiments will be aided by the hybridization of optimal design methods with computationally intensive stochastic simulations. This will take advantage of optimizing the experimental design and leave the task of evaluating the probable real-world performance of a limited number of candidate trial designs and analysis procedures.
Research Interests: Pharmacology, Research Design, Clinical Trial, Drug Discovery, Pharmacokinetics, and 15 moreModeling and Simulation, Clinical Pharmacology, Drug development, Experimental Design, Medicine, Simulation, Software, Humans, Computer Simulation, Stochastic Simulation, Lessons Learned, Optimal Design, Drug Effects, Clinical Trials as Topic, and Pharmacology and pharmaceutical sciences
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Twenty years ago, target concentration intervention (TCI) was distinguished from therapeutic drug monitoring (TDM). It was proposed that TCI would bring more clinical benefit because of the precision of the approach and the ability to... more
Twenty years ago, target concentration intervention (TCI) was distinguished from therapeutic drug monitoring (TDM). It was proposed that TCI would bring more clinical benefit because of the precision of the approach and the ability to link TCI to principles of pharmacokinetics and pharmacodynamics to predict the dose required by an individual (1). We examine the theory and clinical trial evidence supporting the benefits of TCI over TDM and conclude that in the digital age TDM should be abandoned and replaced by TCI.
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In the isolated rat vas deferens stimulated at 0.2 Hz, a series of 2'-, 3'-, and 5'-substituted adenine nucleotides all inhibited the twitch responses, their actions being potentiated by the nucleoside transport... more
In the isolated rat vas deferens stimulated at 0.2 Hz, a series of 2'-, 3'-, and 5'-substituted adenine nucleotides all inhibited the twitch responses, their actions being potentiated by the nucleoside transport inhibitors, HNBTGR, NBMPR and dipyridamole. The metabolism of these nucleotides was examined utilizing HPLC analysis of the bathing medium after exposure to 30 microM nucleoside or nucleotide for 5 min. 5'-AMP, 5'-ADP, 5'-ATP, and NAD+ were all partially hydrolysed to adenosine, the relative extent of this being 5'-AMP greater than 5'-ADP = 5'-ATP greater than NAD+. However, the other nucleotides examined were not detectably converted to adenosine or to adenosine deamination products. These results indicate that the 2'-, 3'- and 5'-substituted nucleotides studied act at a P1-purinoceptor in rat vas deferens to inhibit neurotransmission and, with the exception of 5'-AMP, 5'-ADP, 5'-ATP and NAD+, all appear to act directly at this receptor. However, the 5'-adenine nucleotides (AMP, ADP and ATP) and NAD+ all appear to act at least partially indirectly subsequent to their hydrolysis to adenosine.
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The concepts of disease progression are discussed in the context of neurological disorders. The importance of understanding the time course of the response to inactive (placebo) treatment is discussed. Disease progression and response to... more
The concepts of disease progression are discussed in the context of neurological disorders. The importance of understanding the time course of the response to inactive (placebo) treatment is discussed. Disease progression and response to placebo treatment both need to be considered before drug effects can be reliably identified. Criteria for distinguishing between symptomatic and disease modifying drug effects are proposed and used to interpret the results of clinical trials in pain, depression, schizophrenia, stroke, Alzheimer's disease and Parkinson's disease.
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Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance... more
Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid Emax model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.
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Computer simulation of clinical trials has evolved over the past two decades from a simple instructive game to “full” simulation models yielding pharmacologically sound, realistic trial outcomes. The need to make drug development more... more
Computer simulation of clinical trials has evolved over the past two decades from a simple instructive game to “full” simulation models yielding pharmacologically sound, realistic trial outcomes. The need to make drug development more efficient and informative and the awareness that many industries make extensive use of simulation in product development have advanced considerably the use of simulation of clinical trials in pharmaceutical product development over the past decade. The structural and stochastic components of trial simulation models are explained as a prelude to a listing of representative simulation projects, reflecting investigative applications of statistical methods, trial design comparisons, and full simulation of new drugs being developed. Lessons learned from these projects are reviewed in the context of their current impact and potential for influencing the future of drug development.
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To evaluate study designs and the influence of dispersion of body size, body composition and maturation of clearance or reliable estimation of allometric exponents. Non-linear mixed effects modeling and parametric bootstrap were employed... more
To evaluate study designs and the influence of dispersion of body size, body composition and maturation of clearance or reliable estimation of allometric exponents. Non-linear mixed effects modeling and parametric bootstrap were employed to assess how the study sample size, number of observations per subject, between subject variability (BSV) and dispersion of size distribution affected estimation bias and uncertainty of allometric exponents. The role of covariate model misspecification was investigated using a large data set ranging from neonates to adults. A decrease in study sample size, number of observations per subject, an increase in BSV and a decrease in dispersion of size distribution, increased the uncertainty of allometric exponent estimates. Studies conducted only in adults with drugs exhibiting normal (30%) BSV in clearance may need to include at least 1000 subjects to be able to distinguish between allometric exponents of 2/3 and 1. Nevertheless, studies including both children and adults can distinguish these exponents with only 100 subjects. A marked bias of 45% (95%CI 41-49%) in the estimate of the allometric exponent of clearance was obtained when maturation and body composition were ignored in infants. A wide dispersion of body size (e.g. infants, children and adults) is required to reliably estimate allometric exponents. Ignoring differences in body composition and maturation of clearance may bias the exponent for clearance. Therefore, pharmacometricians should avoid estimating allometric exponent parameters without suitable designs and covariate models. Instead, they are encouraged to rely on the well-developed theory and evidence that clearance and volume parameters in humans scale with theory-based exponents.
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High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose... more
High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5...
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Germovsek and colleagues have recently concluded that a standard approach to modelling pharmacokinetics is not wrong and appears to be at least as useful as other ad hoc methods for describing drug concentrations. There are other... more
Germovsek and colleagues have recently concluded that a standard approach to modelling pharmacokinetics is not wrong and appears to be at least as useful as other ad hoc methods for describing drug concentrations. There are other advantages of this approach including learning about biology, comparing different studies, detecting errors and rationalizing dose prediction. A standard approach to size and maturation is not a panacea but provides the framework for challenging new ideas and supports a consistent method of dosing in patients of all ages.
The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. Clinical data were obtained from 264 patients. Total concentrations for S- and... more
The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks. Warfarin PK was described using a one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small diffe...
The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. PK modeling was used... more
The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. PK modeling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3. A 2-compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by a Imax model with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows: (D1 + D2 ) + ALPHA ×(D1 × D2 ). D1 and D2 are the predicted drug effe...
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This study aims to characterize the influence of body weight and composition on the pharmacokinetics of dexmedetomidine. Twenty obese patients and 20 non-obese patients scheduled for elective laparoscopic surgery were given... more
This study aims to characterize the influence of body weight and composition on the pharmacokinetics of dexmedetomidine. Twenty obese patients and 20 non-obese patients scheduled for elective laparoscopic surgery were given dexmedetomidine infusion schemes. Venous blood samples were taken during and after dexmedetomidine administration. Population pharmacokinetic modeling was undertaken to investigate fat free mass (FFM) and normal fat mass (NFM) as size descriptors of volumes and clearances using non-linear mixed effects modeling. NFM partitions total body weight into FFM and fat mass calculated from total body weight (TBW) minus FFM. The relative influence of fat mass compared to FFM is described by the fraction of fat mass that makes fat equivalent to FFM (Ffat). Theory-based allometric scaling using FFM best described weight and body composition differences in clearances and volumes A negative effect of fat mass of with an exponential parameter of -0.00541/kg (95 % CI -0.0118 to...
Research Interests: Obesity, Adolescent, Humans, Female, Body Composition, and 7 moreMale, Young Adult, Middle Aged, Dexmedetomidine, Adult, Body Weight, and Laparoscopy
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The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice... more
The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (Tabs) of 2.02 h (31)...
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Purpose: To describe the bias and imprecision of t1/2 when CL and V are simulated with and without correlations in the random effects (PPV) and standard errors of parameter estimates (SEE). Methods: PK data for a 1-compartment IV bolus... more
Purpose: To describe the bias and imprecision of t1/2 when CL and V are simulated with and without correlations in the random effects (PPV) and standard errors of parameter estimates (SEE). Methods: PK data for a 1-compartment IV bolus model parameterized with CL (10 L/h, PPV=31.6%) and V (50 L, PPV = 31.6%), with and without correlation (R) between CL
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6 Dose Response: PharmacokineticPharmacodynamic Approach NICK HOLFORD 6.1 Exposure Response ... One way it might be defined is if the same total dose is given with dif-ferent dosing schedules and the cumulative response varies then this... more
6 Dose Response: PharmacokineticPharmacodynamic Approach NICK HOLFORD 6.1 Exposure Response ... One way it might be defined is if the same total dose is given with dif-ferent dosing schedules and the cumulative response varies then this is sched-ule dependence. ...
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A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of... more
A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of the actual trial until after the simulations were submitted to the holder of the trial results. Data from two clinical investigations of quetiapine in patients with schizophrenia were analyzed by use of nonlinear mixed effects modeling to derive a population pharmacokinetic- and pharmacodynamic-based simulation model. The time course of quetiapine concentrations was described by use of a one-compartment open linear pharmacokinetic model with first-order absorption and elimination. The combination of an inhibitory maximum effect pharmacodynamic model for the active treatment effect and a linear function of time for the placebo effect characterized the observed time course of change in the Brief Psychiatric Rating Scale. Simulation results were compared with those in the actual trial to evaluate how well the simulations predicted the outcome. The actual trial results for all doses except the placebo group fell within the predicted Brief Psychiatric Rating Scale scores +/- 1 SE. Unlike the phase 2 trial, from which the pharmacokinetic/pharmacodynamic model was developed, the placebo group in the actual phase 3 trial showed deterioration of Brief Psychiatric Rating Scale scores with time. We conclude that variable placebo responses observed in short-term studies of schizophrenia provide an inadequate basis for the modeling and simulation of placebo subjects in clinical trials. Knowledge of the range of placebo response observed in other studies may have provided an improved basis for the placebo effect model. The model for active drug produced adequate predictions of the actual trial outcomes.
Research Interests: Algorithms, Schizophrenia, Clinical Trial, Placebo Effect, Modeling and Simulation, and 11 moreLinear models, Humans, First-Order Logic, Retrospective Studies, Simulation Model, Time Course, Predictive value of tests, Monte Carlo Method, Treatment Effect, Multicenter Studies as Topic, and Randomized Controlled Trials as Topic
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Our objective was to describe the pharmacokinetics and pharmacodynamics of topotecan in patients. Data were pooled from 9 clinical trials. Topotecan, as a single-agent therapy, was administered as a daily 30-minute intravenous infusion... more
Our objective was to describe the pharmacokinetics and pharmacodynamics of topotecan in patients. Data were pooled from 9 clinical trials. Topotecan, as a single-agent therapy, was administered as a daily 30-minute intravenous infusion for 5 days on a 3-week cycle. Doses of 0.2 to 2.0 mg/m(2) were studied; concentration and neutropenic event data were obtained on multiple occasions. The pharmacokinetics were characterized with use of hierarchical nonlinear regression. The relationship between severity of neutropenia and exposure was characterized with use of logistic regression. The pharmacokinetics of topotecan were described with a linear 2-compartment model. Compromised renal function, low body weight, and poor Eastern Cooperative Oncology Group performance status were determinants of lower clearance, resulting in elevated exposure. Application of covariates reduced interpatient variability in clearance. Logistic regression showed that topotecan area under the concentration-time curve from 0 to 24 hours was predictive of the severity of neutropenia; the only other significant covariate was the number of courses of previous treatment with platinum-based regimens. Patients with compromised renal function, low body weight, or poor performance status had low topotecan clearance. Patients with high topotecan AUC had an increased probability of experiencing severe neutropenia, which was greater if the patient had been pretreated with platinum-based agents. The use of covariates to individualize dose would result in less variability in exposure, reducing the likelihood of severe neutropenia and potentially improving treatment benefit.
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A formal training program in pharmacometrics is essential to train clinical pharmacology scientists. A proposal is made for a pharmacometrics curriculum. The curriculum has components at the undergraduate, graduate and postgraduate levels.
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The clinical pharmacology of antidepressant drugs is challenging to describe because of difficulties in describing the depressed state, the time course of response to a treatment intervention, and the frequent withdrawal of patients from... more
The clinical pharmacology of antidepressant drugs is challenging to describe because of difficulties in describing the depressed state, the time course of response to a treatment intervention, and the frequent withdrawal of patients from clinical trials. Many of these challenges were addressed in a recent article by Russu et al. in this journal.