Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis.

BACKGROUND: We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. . METHODS: A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥ grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table. RESULTS: Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%-22% vs 5%, 4%-7%) and severe anemia (15%, 12%-17% vs 1%, 0%-2%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, <1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a >10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%-72%) of severe anemia. CONCLUSIONS: Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.

Single Ascending-Dose Study To Evaluate the Safety, Tolerability, and Pharmacokinetics of Sutezolid in Healthy Adult Subjects.

The primary objective of the study was to evaluate the safety and tolerability of single oral doses of sutezolid tablets administered under fasting conditions in healthy adult subjects. The secondary objective was to determine the pharmacokinetics (PK) of sutezolid and two metabolites, PNU-101603 and PNU-101244. Overall, sutezolid was well tolerated when administered as a 300-mg, 600-mg, 1,200-mg, or 1,800-mg dose in healthy adult subjects under fasting conditions. Maximum concentration (Cmax) of sutezolid, PNU-101603, and PNU-101244 increased in a less-than-proportional manner with an increase in sutezolid dose between 300 mg and 1,800 mg. Total exposure (AUClast [area under the concentration-time curve from time zero to the time of the last quantifiable concentration] and AUCinf [area under the plasma concentration time curve from time zero extrapolated to infinity]) of sutezolid, PNU-101603, and PNU-101244 increased proportionally with an increase in sutezolid dose.

An Exposure-Response Perspective on the Clinical Dose of Pretomanid.

Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this recommended dose by means of exposure-response (E-R) modeling applied to outcomes of both efficacy and safety. Cox proportional-hazards modeling was used, with the steady-state average pretomanid concentration as the exposure metric. The efficacy outcome was time to sputum culture conversion (TSCC) to negative. The safety outcomes were times to the first occurrence of adverse events in classes selected from either pretomanid's investigator brochure or the new drug application (NDA) submission as recognized safety signals for pretomanid based on preclinical as well as clinical experience. Significant E-R relationships were found for TSCC and two adverse-event classes, vomiting (a single preferred term) and gastrointestinal (GI) symptoms (a collection of related terms). No significant E-R relationships were found for the single preferred terms nausea, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and headache and for the collections hepatic disorders, transaminases increased, skin and subcutaneous tissue disorders, and headache. The results suggest that the recommended dose of pretomanid, 200 mg given in the fed state, is appropriate over the range of pharmacokinetic exposures.

Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis.

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log10(CFU). We also assessed the safety and pharmacokinetics of the study treatments. We found that bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1,200 mg QD (4.5%; 95% Bayesian confidence interval [BCI], 3.3 to 5.6), followed by 600 mg BD (4.1%; BCI, 2.5 to 5.7), 600 mg QD (4.1%; BCI, 2.9 to 5.3), 300 mg BD (3.3%; BCI, 1.9 to 4.7), 300 mg QD (2.3%; BCI, 1.1 to 3.5), and 1,200 mg TIW (2.2%; BCI, 1.1 to 3.3). Similar results were seen with bactericidal activity characterized by the daily rate of change in CFU count. Antimycobacterial activity correlated positively with plasma drug exposure and percentage time over MIC. There were no unexpected adverse events. All linezolid doses showed bactericidal activity. For the same total daily dose, once-daily dosing proved to be at least as effective as a divided twice-daily dose. An intermittent dosing regimen, with 1,200 mg given three times weekly, showed the least activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02279875.).

Population Pharmacokinetics of the Antituberculosis Agent Pretomanid.

A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months. Pretomanid pharmacokinetic behavior was described by a one-compartment model that at a given dose was linear in its absorption and clearance processes but where the rate of absorption and extent of bioavailability changed with dose. Clearance and volume of distribution scaled allometrically with weight. Apparent clearance in females was 18% less than in males. Among HIV-positive subjects, absent the effect of CYP3A4-inducing antiretrovirals, apparent clearance was 6% higher. Some effects of total bilirubin and albumin were found, but the impacts on exposure were small. Bioavailability in the fasted condition was about half that in the fed condition. Relative bioavailability decreased with increasing dose in the fasted condition, but not for doses of ≤200 mg in the fed condition. HIV-positive subjects taking efavirenz and lopinavir/ritonavir had exposures that were reduced by 46 and 17%, respectively. There was little evidence for noteworthy effects of regimen partners on pretomanid. Standard diagnostics indicated that the model described the voluminous, diverse data well, so that the model could be used to generate exposure metrics for exposure/response analyses to be reported elsewhere.

Daily Dosing for Bedaquiline in Patients with Tuberculosis.

The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks. Most TB antibiotics administered with bedaquiline are given QD. Using pharmacokinetic simulations, we explored alternative QD bedaquiline regimens and determined that 200 mg QD for 8 weeks followed by 100 mg QD provides comparable exposures to the approved regimen. This simpler regimen is under clinical evaluation.

Long-Term Effects on QT Prolongation of Pretomanid Alone and in Combinations in Patients with Tuberculosis.

Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.

Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory Emax function of Cmin on the seizure mean, where Emax exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.

Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors.

PURPOSE: The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma. METHODS: A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat. RESULTS: A total of 7834 samples from 581 patients were analyzed. Panobinostat pharmacokinetic parameters were best characterized by a three-compartment model with first-order absorption and elimination. Bioavailability was 21.4 %. Median clearance was 33.1 L/h. Interindividual variability in clearance was 74 %. For Caucasian patients of median age 61 years, area under the curve (AUC) decreased from 104 to 88 ng · h/mL as body surface area (BSA) increased from the first to third quartiles, 1.8 to 2.1 m(2). For Caucasian patients of median BSA 1.9 m(2), AUC decreased from 102 to 95 ng · h/mL as age increased from the first to third quartiles, 51 to 70 years. For patients of median BSA and median age, AUC ranged across the four race categories from 80 to 116 ng · h/mL. Covariate analysis showed no impact on panobinostat clearance and volume by patients' sex, tumor type, kidney function, liver markers, or coadministered medications. However, separate analyses of dedicated studies have demonstrated effects of liver impairment and CYP3A4 inhibition. CONCLUSIONS: Although covariate analyses revealed significant effects of body size, age, and race on panobinostat pharmacokinetics, these effects were minor compared to the interindividual variability and therefore not clinically relevant when dosing panobinostat in populations similar to those studied.

Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling.

BACKGROUND AND INTRODUCTION: The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose. METHODS: Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods. RESULTS: A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively. CONCLUSION: Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis.

BACKGROUND: Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV(1)) are correlated with changes in patient-reported outcomes. METHODS: Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George's Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV(1). Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use. RESULTS: With increasing positive ΔFEV(1), TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV(1) was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV(1) and outcomes. CONCLUSIONS: These results suggest that larger improvements in FEV(1) are likely to be associated with larger patient-reported benefits across a range of clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00393458, NCT00463567, and NCT00624286.

Phase 1 Study of the Effects of the Tuberculosis Treatment Pretomanid, Alone and in Combination With Moxifloxacin, on the QTc Interval in Healthy Volunteers.

Tuberculosis (TB) continues to be a serious threat to public health throughout the world. Newer treatments are needed that could offer simplified regimens with activity against both drug-sensitive and drug-resistant bacilli, while optimizing safety. Pretomanid (PA-824), a nitroimidazooxazine compound, is a new drug for the treatment of pulmonary TB that was recently approved in the United States and Europe in the context of a regimen combined with bedaquiline and linezolid. This phase 1 double-blind, randomized, placebo-controlled crossover study specifically examined the effect of single-dose administration of pretomanid 400 or 1000 mg and pretomanid 400 mg plus moxifloxacin 400 mg on the QTc interval in 74 healthy subjects. Subjects were fasting at the time of drug administration. Pretomanid concentrations following single 400- or 1000-mg doses were not associated with any QT interval prolongation of clinical concern. Moxifloxacin did not alter the pharmacokinetics of pretomanid, and the effect of pretomanid 400 mg plus moxifloxacin 400 mg on the individually corrected QT interval was consistent with the effect of moxifloxacin alone. Both drugs were generally well tolerated. Although supratherapeutic exposure of pretomanid relative to the now-recommended dosing with food was not achieved, these findings contribute to the favorable assessment of cardiac safety for pretomanid.

A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times.

BACKGROUND: Correlation analyses have demonstrated that maintaining an adequate imatinib (IM) trough concentration would be important for clinical response in patients with chronic myeloid leukemia (CML) and Kit-positive gastrointestinal stromal tumors. The objectives of the current work were to use a pharmacokinetic model to refine the trough levels obtained at different sampling times and to propose a therapeutic drug monitoring algorithm and an acceptable sampling time window for imatinib trough sampling. METHODS: The pharmacokinetics of IM in patients (pts) with CML were characterized based on historical data from a Phase III study. In the elimination phase the concentration of IM (C(t)) follows a mono-exponential decline, and the standardized trough concentration (C(min,std) = C(tau)) can be described by a simple algorithm C(min,std) = C(t)* exp(k(e) x Delta t), where Delta t = t - tau, and tau is 24 hours for qd or 12 hours for bid dosing and k(e) is the elimination rate constant. The percent deviation of C(t) from C(min,std) was simulated for different Delta t and k(e) values to define a sampling time window Delta t, within which the percent deviation is <20%. RESULTS: Simulation analysis shows that C(t) is largely dependent on Delta t and k(e). The percent deviation of C(t) at 3 hours before or after tau from C(min,std) will be 7.1%, 13.1%, and 23.4% for pts with low, typical, and high k(e) values, 0.023/hour, 0.041/hour, and 0.070/hour, respectively. However, if a correction is made for C(t) by the algorithm using the typical k(e) value of 0.041 per hour, the percent deviation at 3 hours will be reduced to 5.3%, 0%, and 9.1% for pts with low, typical, and high k(e) values, respectively. Even if the sampling window is extended to +/-6 hours, the corresponding percent deviation will still be reasonable: 10.2%, 0%, and 19.0%, respectively. CONCLUSION: By using the algorithm, the pharmacokinetic sampling window can be extended to a wider window to make the trough sampling easy to implement in the clinical setting, provided that the sampling time and dosing time are accurately recorded.

Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing's Disease Patients.

BACKGROUND AND OBJECTIVE: Pasireotide (SOM230, Signifor®) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics. METHODS: The analysis dataset included five phase I studies and one each from phase II and phase III. A three-compartment, linear structural pharmacokinetic model was used. Models were specified a priori that varied in the relationship between HVs and CDPs, and the model with the lowest value of the Bayes Information Criterion (BIC) was selected. It was then used to illustrate various features of pasireotide pharmacokinetics. RESULTS AND CONCLUSIONS: In the final model, the estimated values of apparent clearance (CL/F), central volume of distribution, and deep peripheral volume of distribution of pasireotide in CDP were 59, 43, and 225% those of HVs at the same age and body size. Clearance increased with body size and decreased with age similarly for CDPs and HVs. The estimated CL/F for a typical CDP (40 years old, lean body weight [LBW] 49 kg) was 3.72 L/h, and for a typical HV (29 years old, LBW 61 kg) was 7.96 L/h. The model was judged adequate by visual predictive checks and diagnostic plots separately for HVs and CDPs and can be used for simulations for deriving exposure-response metrics for pharmacokinetic/pharmacodynamic analyses.

Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors.

PURPOSE: Sonidegib (Odomzo) selectively inhibits smoothened and suppresses the growth of hedgehog pathway-dependent tumors. A population pharmacokinetic (PK) analysis of sonidegib in healthy subjects and patients with advanced solid tumors was conducted to characterize PK, determine variability, and estimate covariate effects. METHODS: PK data from five phase 1 or 2 studies (N = 436) in the dose range from 100 to 3000 mg were analyzed using NONMEM. A two-compartment base model with first-order absorption, lag time, linear elimination, and bioavailability that decreased with dose was updated to describe the PK of sonidegib. Covariate analyses were performed and were incorporated into the population PK full model. RESULTS: The base and full models were robust with a good fit to the study data. Population-predicted geometric means (inter-individual variability, CV%) of apparent oral clearance, apparent volume of distribution at steady state, accumulation ratio, and elimination half-life were 9.5 L/h (71.4 %), 9163 L (74.9 %), 21 (131 %) and 29.6 days (109 %). Clinically relevant covariate effects were: A high-fat meal increased sonidegib bioavailability fivefold, healthy volunteers had threefold higher clearance, sonidegib bioavailability decreased with increasing dose levels, and PPI coadministration reduced sonidegib bioavailability by 30 %. Sonidegib PK was not significantly impacted by baseline age, weight, total bilirubin, alanine aminotransferase, albumin, creatinine clearance, gender, and ethnicity (Western countries versus Japanese). CONCLUSION: No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications.

Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly.

OBJECTIVE: Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients. METHODS: In a double-blind, 3-period, crossover, proof-of-concept study, 12 patients with active acromegaly were randomized to single subcutaneous doses of SOM230 (100 and 250 microg) and octreotide (100 microg). Concentrations of SOM230, octreotide, and GH were determined at designated times after dosing and at baseline. The PK properties of SOM230 and octreotide and the relationship of PK with GH were investigated by a nonlinear mixed-effects modeling analysis. RESULTS: The apparent clearance for SOM230 is approximately half of that for octreotide (8.0 L/h versus 15.8 L/h). The elimination half-life for SOM230 is about 5 times longer than that for octreotide (11.8 hours versus 2.3 hours). The relationship between GH levels and plasma concentrations of SOM230 and octreotide is well described by a direct inhibitory model. The test drug concentration level at which half of the maximum drug effect is observed (EC50) is 46 and 553 pg/mL for octreotide and SOM230, respectively, with large interpatient variability (coefficients of variation, 164% and 65%, respectively), mainly attributable to the heterogeneous responses among patients. CONCLUSIONS: SOM230 demonstrates a lower clearance and longer half-life than octreotide, which compensates for the lower potency in GH inhibition. As a result of the lower interpatient variability for EC50 , SOM230 is expected to have a more uniform clinical GH inhibition than octreotide for acromegalic patients at a clinically effective dosing regimen.

Diagnostics for confounding in PK/PD models for oxcarbazepine.

One type of pharmacokinetic/pharmacodynamic (PK/PD) relationship that is used to characterize the therapeutic action of a drug is the relationship between some univariate summary of the plasma-concentration-versus-time profile and the drug effect on a response outcome. Operationally, such a relationship may be observed in a large clinical trial where randomly sampled patients are randomized to different values of the concentration summary. If, under such conditions, the relationship between concentration and effect does not depend on the dose needed to attain the target concentration, such a relationship will be called a true PK/PD relationship. When the true PK/PD relationship is assessed as an object of estimation in a dose-controlled clinical trial (i.e. when dose is randomized), observed drug concentration is an outcome variable. The estimated PK/PD relationship between observed outcome and observed concentration, which we then refer to as the conventional PK/PD relationship, may be biased for the true PK/PD relationship. Because of this bias, the conventional relationship is called confounded for the true one. We show that diagnostics for confounding can be devised under reasonable assumptions. We then apply these diagnostics to PK/PD assessments of adults and children on oxcarbazepine adjunctive therapy. It was necessary to demonstrate the similarity of the true PK/PD relationships of adults and children on adjunctive therapy in order to support the approval of oxcarbazepine monotherapy in children by a bridging argument.

On some "disadvantages" of the population approach.

In a seminal article on population pharmacokinetic modeling, researchers demonstrated how means and variances of pharmacokinetic parameters for a patient population could be inferred from sparse data collected under conditions of routine patient care. But they also identified 4 potential concerns about their methodology: unobserved confounding variables may bias the inferences; conditions under which data are collected may lead to inaccuracies of reporting or recording; correlations among important predictor variables may reduce statistical efficiency; and costs cannot be controlled by principles of study design. Experiences are reviewed that relate to these potential disadvantages. A method is presented for diagnosing the possible presence of confounding. A model is constructed and applied that captures the influences of data inaccuracies. An example of selecting from among correlated covariates is summarized. Finally, a methodology for optimal study design is reviewed and applied to an example.