Long-term follow-up of patients with Herlitz-type junctional epidermolysis bullosa.

BACKGROUND: Junctional epidermolysis bullosa, type Herlitz (JEB-H) is a rare, autosomal recessive disease caused by absence of the epidermal basement membrane adhesion protein laminin-332. It is characterized by extensive and devastating blistering of the skin and mucous membranes, leading to death in early childhood. OBJECTIVES: To present the results of the long-term follow-up of a cohort of patients with JEB-H, and to provide guidelines for prognosis, treatment and care. METHODS: All patients with JEB-H included in the Dutch Epidermolysis Bullosa (EB) Registry between 1988 and 2011 were followed longitudinally by our EB team. Diagnosis was established using immunofluorescence antigen mapping, electron microscopy and DNA analysis. RESULTS: In total, we included 22 patients with JEB-H over a 23-year period. Their average age at death was 5.8 months (range 0.5-32.6 months). The causes of death were, in order of frequency: failure to thrive, respiratory failure, pneumonia, dehydration, anaemia, sepsis and euthanasia. The pattern of initial weight gain was a predictor of lifespan in these patients. Invasive treatments to extend life did not promote survival in our patients. CONCLUSIONS: It is important to diagnose JEB-H as soon as possible after birth so that the management can be shifted from life-saving to comfort care. The palliative end-of-life care can take place in hospital, but is also safe in the home setting. Suffering in patients with JEB-H can become so unbearable that in some patients who do not respond to adequate analgesic and sedative treatment, newborn euthanasia, performed according to the Groningen protocol, is legally permitted in the Netherlands.

[Anaphylaxis in two children caused by peanut and nut allergies; recommendations for treatment]. / Anafylaxie door pinda- en notenallergie bij 2 kinderen; aanbevelingen voor beleid.

Two girls aged 12 and 7 years with asthma and peanut and nut allergy developed anaphylactic shock after ingestion of peanuts and nuts from an unreported source. They were both given intramuscular epinephrine. The 12-year-old girl was treated clinically for shock and after two days was discharged from hospital. The 7-year-old girl died. Risk factors for life-threatening anaphylactic reactions are adolescent to young adult age, asthma, previous severe anaphylactic reactions to the food in question, previous reaction to small dose of the food in question and allergy to peanuts or tree nuts. A double-blind, placebo-controlled food challenge should be carried out to document the culprit food. The most important therapeutic intervention is the intramuscular administration of epinephrine. For patients with two or more risk factors the prescription of an epinephrine auto-injector should be considered.

Direct Oral Anticoagulants Vs. Enoxaparin for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose-Response Meta-analysis.

We carried out a dose-response model-based meta-analysis to assess venous thromboembolism (VTE) and bleeding with factor Xa (FXa) inhibitors (apixaban, edoxaban, rivaroxaban) and a thrombin inhibitor (dabigatran) compared with European (EU) (40 mg q.d.) and North American (NA) (30 mg Q12H) dose regimens of a low molecular weight heparin (enoxaparin) following orthopedic surgery. Statistically significant differences in both VTE and bleeding outcomes were found between the NA and EU doses of enoxaparin, with odds ratios (95% confidence interval) for the NA vs. EU dose of 0.73 (0.71-0.76) and 1.20 (1.14-1.29) for total VTE and major bleeding, respectively. At approved doses, estimated odds ratios vs. both doses of enoxaparin for the three FXa inhibitors (range: 0.35-0.75 for VTE; 0.76-1.09 for bleeding) compared with those for dabigatran (range: 0.66-1.21 for VTE; 1.10-1.38 for bleeding) suggested generally greater efficacy and less bleeding for the FXa inhibitors.

Quantitative Evaluations of Time-Course and Treatment Effects of Systemic Agents for Psoriasis: A Model-Based Meta-Analysis.

Aggregate data model-based meta-analysis is a regression approach to compare the dose-response and/or time-course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose-response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12. Body weight exhibited an inverse effect on the placebo component of both models, suggesting that body weight affects the overall PASI response regardless of drug. This analysis provides a quantitative framework for efficacy comparisons across psoriasis treatments.

Population pharmacodynamic model for ketorolac analgesia.

OBJECTIVE: To derive a population pharmacokinetic-pharmacodynamic model that characterizes the distribution of pain relief scores and remedication times observed in patients receiving intramuscular ketorolac for the treatment of moderate to severe postoperative pain. BACKGROUND: The data analysis approach deals with the complexities of analyzing analgesic trial data: (1) repeated measurements, (2) ordered categorical response variables, and (3) nonrandom censoring because the patients can take a rescue medication if their pain relief is insufficient. METHODS: Patients (n = 522) received a single oral or intramuscular administration of placebo or a single intramuscular dose of 10, 30, 60, or 90 mg ketorolac for postoperative pain relief. Pain relief was measured periodically with use of a five-category ordinal scale up to 6 hours after dosing. In this period, 288 patients received additional medication because of insufficient pain relief. Pharmacokinetic data was available for 85 subjects. Models were fitted to the data with the NONMEM program. RESULTS: The pharmacokinetic data was best described by a two-compartment model with first-order absorption. Pain relief was found to be a function of drug concentration (Emax model), time (waxing and waning of placebo effect), and an individual random effect. The drug concentration at half-maximal effect (EC50) and the first-order rate constant (keo) half-life for pain relief were 0.37 mg/L and 24 minutes. The probability of remedication was found to be a function of the observed level of pain relief and was found to increase with time. Monte Carlo simulations showed that adequate pain relief was achieved in 50% of the patients at 41, 27, 23, and 21 minutes after 10, 30, 60, or 90 mg of intramuscular ketorolac. Adequate pain relief was maintained up to 6 hours in 50%, 70%, 78%, and 81% of patients after these four doses. Only 25% of the patients achieved adequate pain relief with placebo. CONCLUSIONS: A population pharmacokinetic-pharmacodynamic model for the analgesic efficacy of intramuscular ketorolac was derived. The simulated relationship between dose, time, and percentage of patients with adequate pain relief suggested that 30 mg intramuscular ketorolac was the optimal initial dose for postoperative pain relief.

Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers.

The pharmacodynamics of midazolam and its main metabolite alpha-hydroxymidazolam were characterized in individual subjects by use of saccadic eye movement and electroencephalographic (EEG) effect measurements. Eight healthy volunteers received 0.1 mg/kg midazolam intravenously in 15 minutes, 0.15 mg/kg alpha-hydroxymidazolam intravenously in 15 minutes, 7.5 mg midazolam orally and placebo in a randomized, double-blind, four-way crossover experiment. Plasma concentrations of midazolam, alpha-hydroxymidazolam and 4-hydroxymidazolam were measured by gas chromatography. The amplitudes in the 11.5 to 30 Hz (beta) frequency band were used as EEG effect measure. The concentration-effect relationships were quantified by the sigmoid maximum effect model. The median effective concentrations of midazolam and alpha-hydroxymidazolam were (mean +/- SE) 77 +/- 15 and 98 +/- 17 ng/ml, respectively, for the EEG effect measure. For peak saccadic velocity the values were 40 +/- 7 ng/ml for midazolam and 49 +/- 10 ng/ml for alpha-hydroxymidazolam. The maximum effect values were similar for both compounds. The effects observed after oral administration of midazolam could not be predicted accurately by an additive and competitive interaction model. It seems that alpha-hydroxymidazolam is highly potent with respect to the measured effects and contributes significantly to those effects of midazolam after oral administration.

Electroencephalogram effect measures and relationships between pharmacokinetics and pharmacodynamics of centrally acting drugs.

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs. An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring. Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from other in vitro and in vivo effect measurements. These comparisons revealed that changes in the amplitudes in the beta frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines, which reflects their affinity and intrinsic efficacy at the central gamma-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.

Differences in intrinsic efficacy of benzodiazepines are reflected in their concentration-EEG effect relationship.

1. The relevance of EEG effect parameters as a measure of the central nervous system effects of benzodiazepines was evaluated. The concentration-EEG effect relationships of the benzodiazepine agonist midazolam, partial agonist bretazenil, antagonist flumazenil and inverse agonist Ro 19-4603 were quantified and compared with the intrinsic efficacy and affinity of these compounds at the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. 2. The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous bolus administration of 5 mg kg-1 midazolam, 2.5 mg kg-1 bretazenil, 10 mg kg-1 flumazenil or 2.5 mg kg-1 Ro 19-4603 to male Wistar derived rats. In a separate experiment the distribution between blood, cerebrospinal fluid and brain concentrations of these compounds was determined. A sensitive assay was developed to measure bretazenil and Ro 19-4603 concentrations in small samples of biological fluids. 3. The benzodiazepine-induced changes in amplitudes in the 11.5-30 Hz frequency band, as determined by aperiodic analysis, was used as EEG effect measure. Concentration-EEG effect relationships were derived by a pharmacokinetic-pharmacodynamic modelling procedure and in the case of midazolam, bretazenil and Ro 19-4603 successfully quantified by the sigmoidal Emax model. Large differences in maximal effect of midazolam (Emax = 73 +/- 2 microVs-1), bretazenil (Emax = 19 +/- 1 microVs-1) and Ro 19-4603 (Emax = -6.5 +/- 0.4 microVs-1) were observed, reflecting their differences in intrinsic efficacy. A close correlation was found between the EC50 values based on free drug concentration and receptor affinity as determined by displacement of [3H]-flumazenil in a washed brain homogenate at 37 degrees C. In the concentration range of receptor saturation flumazenil did not produce any changes in the EEG effect measure.4. The study demonstrated that the change in amplitudes in the 11.5-30 Hz frequency band of the EEG is a relevant measure of the pharmacological effect intensity of benzodiazepines, because it seems to reflect their affinity and intrinsic efficacy at the central GABA-benzodiazepine receptor complex.

Pharmacokinetic-pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration.

1. The purpose of the present investigation was to quantify the concentration-pharmacological effect relationship of midazolam in individual rats by use of effect parameters derived from aperiodic EEG analysis. By varying the rate and route of administration the role of (inter)active metabolites and development of acute tolerance was evaluated. 2. The pharmacokinetics and pharmacodynamics of midazolam were determined after intravenous administration of 10 mg kg-1 during 5, 30 and 60 min and oral administration of 15 mg kg-1. Following intravenous administration the pharmacokinetics were most adequately described by a bi-exponential equation. The values (mean +/- s.e. mean, n = 20) of clearance, volume of distribution at steady-state and terminal half-life were 67 +/- 2 ml min-1 kg-1, 1.61 +/- 0.071 kg-1 and 27 +/- 1 min, respectively. Following oral administration midazolam was rapidly absorbed with a systemic availability of 45 +/- 9%. 3. The averaged amplitudes in the 11.5-30 Hz (beta) frequency band of the fronto-central lead on the left-hemisphere, as derived by aperiodic EEG analysis, was selected as a measure of the pharmacological effect of midazolam. By pharmacokinetic-pharmacodynamic modelling the individual concentration-EEG effect relationships of midazolam were derived, which were successfully quantified by the sigmoidal Emax model. No marked and systematic differences in pharmacodynamic parameters were found between the rates and routes of administration. The averaged pharmacodynamic parameters of midazolam obtained after combining the results of all rates and routes of administration were (mean + s.e.mean, n = 27): Eo = 61 + 3puV s 1, Emax = 85 + 3 Vs 1, EC50 = 40 + 3 ngmlP-1 and N = 0.84 + 0.04. 4. The results of the present study show that the concentration-EEG effect relationship of midazolam can be characterized in individual animals using the amplitudes in the 11.5-30 (beta) frequency band as a measure of pharmacological response. Acute tolerance did not develop and (inter)active metabolites did not contribute to this effect parameter within the time span of the experiments.

Pharmacokinetic-EEG effect relationship of midazolam in aging BN/BiRij rats.

1. The purpose of the present investigations was to determine the influence of increasing age on the pharmacokinetics and pharmacodynamics of midazolam in male BN/BiRij rats as an animal model of aging. 2. Midazolam was administered intravenously at a dose of 2.5 mg kg-1 and its pharmacokinetics were determined on the basis of plasma concentrations as measured by high performance liquid chromatography (h.p.l.c.). Pharmacodynamics were studied using the midazolam-induced changes in the electro-encephalogram (EEG) as a measure of the pharmacological effect. Results were evaluated on the basis of simultaneous pharmacokinetic-pharmacodynamic modelling. In an attempt to differentiate between the effects of aging and of concurrent disease, an extensive clinical biochemical/pathological examination was conducted in individual rats by an independent pathologist. 3. The pharmacokinetics of midazolam were best characterized on the basis of a two exponential model. In the 4-month-old rats the values of the clearance, volume of distribution and elimination half-life were 104 +/- 13 ml min-1 kg-1 (mean +/- s.e. mean), 3.4 +/- 0.7 l kg-1 and 30 +/- 3 min, respectively. With increasing age, no changes in the pharmacokinetics of midazolam were observed. 4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/- 6 micrograms l-1 and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed.4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/-6 lg 1' and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed. However, when diseased animals were excluded from the evaluation, a tendency towards a decrease in the midazolam concentration at half maximum effect to 25 +/- 14 pg 1-1 was observed in the 36-month-old rats.5. These findings suggest, that increasing age is associated with a tendency towards an increased brain sensitivity to midazolam, which is reflected in a parallel shift of the concentration vs. EEG effect relationship towards lower concentrations. However, it appears that factors other than age also contribute to interindividual variability in pharmacodynamics, considering the substantial interindividual variability within certain age groups.

Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.

1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated.

Stability and pharmacokinetics of flumazenil in the rat.

The pharmacokinetics of flumazenil in the rat were determined after 2.5 mg/kg intravenous and 25 mg/kg oral administration. Following intravenous administration flumazenil was rapidly eliminated with an extremely short terminal half-life (mean +/- SE, n = 8) of 8.3 +/- 0.3 min due to a large total blood clearance of 147 +/- 7 ml/kg/min combined with a relatively small volume of distribution at steady-state of 1.33 +/- 0.07 l/kg. After oral administration flumazenil was rapidly absorbed; however, the bioavailability was low (28 +/- 4%) and variable. Flumazenil was found to be unstable in rat blood in vitro and disappeared with a half-life (mean +/- SE, n = 5) of 8.3 +/- 1 min and 31 +/- 4 min at body and room temperature, respectively. The blood samples were stabilized by addition of sodium fluoride (NaF) and cooling to 0 degrees C. The samples had to be stored at -35 degrees C when analyzed at later times. Presumably esterases in rat blood are responsible for the observed instability. A sensitive HPLC assay to measure flumazenil concentrations in small blood samples is also described.

Pharmacodynamic interaction between midazolam and a low dose of ethanol in vivo.

The pharmacokinetic and pharmacodynamic interactions between midazolam and ethanol were studied in the rat in vivo. Ethanol was given as a constant rate intravenous infusion (1.85 mg/min). The pharmacokinetics and pharmacodynamics of midazolam were determined following an intravenous dose of 5 mg/kg in 15 minutes. Amplitudes in the 11.5-30 Hz (beta) frequency band of the EEG was used as a measure of the pharmacological effect. Ethanol infusion resulted in a constant plasma alcohol concentration of 0.44 +/- 0.04 g/l (Mean +/- SE) and had no effect on the baseline value of the EEG effect parameter. Also the pharmacokinetics of midazolam were unchanged. However, a significant parallel shift of the midazolam concentration-EEG effect relationship to lower concentrations was observed. These findings show that there is a pharmacodynamic interaction between midazolam and ethanol in vivo.

A system approach to pharmacodynamics. III: An algorithm and computer program, COLAPS, for pharmacodynamic modeling.

Many pharmacodynamic (PD) models may be generalized in the form E(t) = N(L[c(t)]), where E(t) is a recorded effect response, c(t) is a sampled drug level, N is a nonlinear autonomic function, and L is a linear operator that commonly is a convolution operation. The NL class of PD models includes the traditional effect compartment PD models as a subclass, but is not limited to such models. An algorithm and computer program named COLAPS, based on system analysis principles and hysteresis minimization, that enable N and L to be empirically determined for the NL class of models without addressing specific kinetic structure aspects ("model independence") are presented. The kinetic concepts of biophase conduction and transduction functions are used by COLAPS. Such an approach is more general than the effect compartment approaches because it does not assume first-order transport principles. The pitfalls of hysteresis minimization in PD modeling are discussed and the procedures taken by COLAPS to avoid these pitfalls are outlined. A transformation technique prevents improper convergence to a point. A novel reparameterization scheme is introduced that maximizes the flexibility of the kinetic functions and extends the generality of the analysis. Inequality function constraints are maintained without the need for troublesome constrained nonlinear optimization procedures. Usage of the COLAPS program is illustrated in the analysis of the PD of amobarbital. The COLAPS program resulted in an excellent minimization of the effect versus biophase level hysteresis. The biophase conduction function, the biophase drug level (normalized), and the transduction curve were determined. The transduction curve showed clear biphasic behavior.

Biophase equilibration times.

Various methods for describing how quickly a drug equilibrates at the biophase are proposed. The biophase equilibration time (BET) is the time it takes the biophase drug level to reach a given percentage (p) of its predicted steady state in a drug administration that leads to a steady-state condition. The time to reach biophase equilibrium may be defined as the BET value for p = 95, and the 50% biophase equilibration time is obtained when p = 50. Biophase equilibration profiles (BEPs), obtained by plotting p versus BET, give a dynamic representation of the approach to equilibrium and may serve as an indicator of the rate of drug delivery to the biophase. A pharmacodynamic system analysis method is proposed to determine BETs and BEPs from the biophase conduction function. The approach is demonstrated using pharmacodynamic data from the CNS effect of amobarbital evaluated by an aperiodic analysis of EEG recordings. The relevance of the BET and/or BEP principles in optimal computer-controlled drug infusion, drug design, and evaluation of targeted drug delivery is discussed. Both vascular and extravascular drug administrations are considered in the analysis.

Determination of dexmedetomidine in rat plasma by a sensitive [3H]clonidine radioreceptor assay.

This paper describes the development and implementation of a sensitive radioreceptor assay (RRA) for determining concentrations of dexmedetomidine, an alpha-2 adrenergic agonist with anesthetic properties, in rat plasma. Calf retina membranes were selected as the alpha-2 adrenergic receptor source, and the alpha-2 antagonist [3H]RX821002 and the alpha-2 agonist [3H]clonidine were evaluated as radioligands. We optimized the binding conditions for both radioligands and chose a radioligand for implementation in the RRA based on the characteristics of the inhibition binding curves with dexmedetomidine. The final method is based on competition between the radioligand [3H]clonidine and dexmedetomidine for high-affinity binding sites present in calf retina membranes. The assay has a coefficient of variation of 8% in the range 23.7-592 pg for 0.2 mL of plasma. This assay can be applied to pharmacokinetic-pharmacodynamic studies of dexmedetomidine.

Pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations: principles and perspectives.

A new approach to preclinical pharmacodynamic investigations is presented which allows, in addition to information on the nature of the pharmacological properties of new chemical entities, also important quantitative pharmacodynamic information to be derived. A single intravenous dose is administered to chronically instrumented rats and the time course of the pharmacological effect is determined in conjunction with plasma or serum concentrations. Datasets obtained in this way are subjected to simultaneous pharmacokinetic/pharmacodynamic modelling to obtain estimates of pharmacodynamic parameters such as EC50, Emax, Hill factor and the rate of biophase equilibration. The new approach was applied in studies with benzodiazepines, baclofen, antiepileptic drugs and adenosine receptor agonists and antagonists. In these studies quantitative EEG parameters, the threshold for convulsion as determined by direct cortical stimulation and various haemodynamic variables were used as a pharmacodynamic endpoint. For drugs exhibiting agonistic or inverse agonistic properties, realistic estimates of the potency and intrinsic efficacy could be obtained by modelling of the direct effects in the various effect models. Estimates of the potency of competitive antagonists (e.g. flumazenil, cyclopentyl-theophylline) could be obtained on the basis of modelling of the pharmacodynamic interaction with a full agonist. For baclofen finally also the rate of biophase equilibration could be estimated. The results of these studies show that by implementation of pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations, useful quantitative information on the pharmacodynamics of new drugs in vivo can be obtained. It is suggested that this information may be of value in the early phases of pre-clinical drug development and that it may facilitate the subsequent clinical development process.

Prediction of clinical irrelevance of PK differences in atorvastatin using PK/PD models derived from literature-based meta-analyses.

To support the development of a fixed-dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature-based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non-clinically significant change of <1.2% absolute difference in the percentage lowering of low-density-lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose-response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.

An adaptive-design dose-ranging study of PD 0348292, an oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery.

BACKGROUND: PD 0348292 is an oral, selective, direct and reversible factor Xa inhibitor. This was an adaptive dose-ranging study evaluating a 100-fold PD 0348292 dose range in subjects undergoing total knee replacement (TKR). OBJECTIVE: To assess the efficacy and safety of a dose range of PD 0348292 relative to enoxaparin for the prevention of venous thromboembolism (VTE). METHODS: Extensive dose-response modeling and trial simulations were used to select the PD 0348292 dose range for the Phase 2 study. Subjects were randomized to a blinded PD 0348292 dose (0.1 mg qd to 10 mg qd) or open-label enoxaparin (30 mg bid) for 6-14 days after TKR surgery. Efficacy was assessed by mandatory bilateral venography. Results were analyzed using a dose-response modeling approach. RESULTS: Observed VTE frequency ranged from 1.4-37.1% across PD 0348292 doses and was 18.1% for enoxaparin. The PD 0348292 dose-response relationship for VTE was statistically significant (P < 0.0001). The dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention was estimated to be 1.16 mg (95% CI = 0.56 mg, 2.41 mg) qd. Total bleeding ranged from 4.9% to 13.8% across PD 0348292 doses and was 6.3% with enoxaparin. The dose-response relationship for total bleeding was not statistically significant (P = 0.2464). Overall, PD 0348292 and enoxaparin were well tolerated. CONCLUSION: Characterization of the dose-response relationship for VTE and bleeding using an adaptive Phase 2 study design provided a strong quantitative basis for Phase 3 dose selection.

Clinical Trial Simulation to Inform Phase 2: Comparison of Concentrated vs. Distributed First-in-Patient Study Designs in Psoriasis.

Clinical trial simulation (CTS) and model-based meta-analysis (MBMA) can increase our understanding of small, first-in-patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose-ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the psoriasis space, a threshold of greater than a 50 percentage point improvement over placebo effect at the highest feasible drug dose was required for the advancement in psoriasis. Studies testing only placebo and the maximum dose made the correct advancement decision marginally more often than dose-ranging designs in the majority of the cases. However, dose-ranging studies in FIP trials offer important design advantages in the form of dose-response (D-R) information to inform Phase 2 dose selection. CTS can increase the efficiency and quality of drug development decision making by studying the limitations and benefits of study designs prospectively.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e58; doi:10.1038/psp.2013.32; published online 24 July 2013.