Design Of Pharmacokinetic Studies Research Articles

Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics.

The transition from intravenous (i.v.) to subcutaneous (s.c.) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology, and regulatory considerations for successful i.v. to s.c. bridging for biologics after the i.v. formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the i.v. and s.c. routes of administrations. Selected key recommendations and points to consider include: (i) PK characterization of the s.c. formulation, supported by the increasing preclinical understanding of the s.c. absorption, and robust PK study design and analyses in humans; (ii) a thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; (iii) comparability studies designed to meet regulatory considerations and support approval of the s.c. formulation, including noninferiority studies with PK and/or efficacy and safety as primary end points; and (iv) comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to s.c. dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.

Topical pharmacokinetics of brinzolamide suspensions in rabbits and variability analysis for sample size and design considerations

Identifying critical attributes for complex locally acting ophthalmic formulations and establishing in vitro-in vivo correlations can facilitate selection of appropriate thresholds for formulation changes that reflect lack of impact on in vivo performance. In this study the marketed antiglaucoma product Azopt® (1% brinzolamide suspension) and five other brinzolamide formulations varying in particle size distributions and apparent viscosities were topically administered in rabbits, and their ocular pharmacokinetics was determined in multiple ocular tissues. Statistical evaluation with ANOVA showed no significant differences between the formulations in the peak drug concentration (Cmax) in the aqueous humor and iris-ciliary body. As a post-hoc analysis, the within animal and total variability was determined for Cmax in the aqueous humor and iris-ciliary body. Based on the observed variability, we investigated the sample size needed for two types of study designs to observe statistically significant differences in Cmax. For the sample size calculations, assuming both 25% and 50% true differences in Cmax between two formulations, two study designs were compared: paired-eye dosing design (one formulation in one eye and another formulation in the other eye of the same animal at the same time) versus parallel-group design. The number of rabbits needed in the paired-eye dosing design are much lower than in the parallel-group design. For example, when the true difference in aqueous humor Cmax is 25%, nine rabbits are required in the paired-eye design versus seventy rabbits (35 per treatment) in the parallel-group design to observe a statistically significant difference with a power of 80%. Therefore, the proposed paired-eye dosing design is a viable option for the design of pharmacokinetic studies comparing ophthalmic products to determine the impact of formulation differences.

Simplifying the Extended Clearance Concept Classification System (EC3S) to Guide Clearance Prediction in Drug Discovery.

The Extended Clearance Concept Classification System was established as a development-stage tool to provide a framework for identifying fundamental mechanism(s) governing drug disposition in humans. In the present study, the applicability of the EC3S in drug discovery has been investigated. In its current format, the EC3S relies on low-throughput hepatocyte uptake data, which are not frequently generated in a discovery setting. A relationship between hepatocyte uptake clearance and MDCK permeability was first established along with intrinsic clearance from human liver microsomes. The performance of this approach was examined by categorizing 64 drugs into EC3S classes and comparing the predicted major elimination pathway(s) to that observed in humans. As an extension of the work, the ability of the simplified EC3S to predict human systemic clearance based on intrinsic clearance generated using in-vitro metabolic systems was evaluated. The assessment enabled the use of MDCK permeability and unscaled unbound intrinsic clearance to generate cut-off criteria to categorize compounds into four EC3S classes: Class12ab, 2cd, 34ab, and 34cd, with major elimination mechanism(s) assigned to each class. The predictivity analysis suggested that systemic clearance could generally be predicted within threefold for EC3S class 12ab and 34ab compounds. For classes 2cd and 34cd, systemic clearance was poorly predicted using in-vitro systems explored in this study. Collectively, our simplified classification approach is expected to facilitate the identification of mechanism(s) involved in drug elimination, faster resolution of in-vitro to in-vivo disconnects, and better design of mechanistic pharmacokinetic studies in drug discovery.

Pharmacokinetic Variability in Pre-Clinical Studies: Sample Study with Abiraterone in Rats and Implications for Short-Term Comparative Pharmacokinetic Study Designs.

One of the major concerns for all in vivo experiments is intra- and inter-subject variability, which can be a great source of inaccuracy. The aim of this study is, therefore, to estimate the ability of parallel vs. cross-over design studies in order to describe the relative pharmacokinetic performance of the studied drug formulations. We analyzed the data from a drug development program that examined the performance of innovative abiraterone acetate formulations against the identical reference product in three stages. In stages 1–3, groups A–F were dosed with the reference product once in a parallel manner. Stage 4 was performed to evaluate the intra-individual variability (IIV) by repeated administration of the reference product to the same animals. Although the geometric mean (90% CI) values of abiraterone AUClast in groups A–F were similar to the IIV group (24.36 (23.79–41.00) vs. 26.29 (20.56–47.00) mg/mL·min·g), the results generated in the isolated parallel groups provided imprecise estimates of the true AUClast values ranging from 9.62 to 44.62 mg/mL·min·g due to chance. Notably, in 4 out of 15 possible pair comparisons between the parallel groups, the confidence intervals did not include 100%, which is the true ratio for all comparisons tested after identical formulation administration to all groups. A cross-over design can significantly improve the methodology in short-term comparative pre-clinical pharmacokinetic studies, and can provide more precise and accurate results in comparison to more traditional pre-clinical study designs.

Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.

Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.

Adapting regulatory drug‐drug interaction guidance to design clinical pharmacokinetic natural product‐drug interaction studies: A NaPDI Center recommended approach

Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies’ guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions.

Guidelines for the experimental design of pharmacokinetic studies with nanomaterials in preclinical animal models

A shared feature in the value proposition of every nanomaterial-based drug delivery systems is the desirable improvement in the disposition (or ADME) and pharmacokinetic profiles of the encapsulated drug being delivered. Remarkable progress has been made towards understanding the complex and multifactorial relationships between pharmacokinetic profiles and nanomaterial physicochemical properties, biological interactions, species physiology, etc. These advances have fuelled the rational design of numerous nanomaterials with long-circulation times and improved tissue accumulation (e.g., in tumours). Unfortunately, a central weakness in many of these research efforts has been the inconsistent and insufficient characterisation of the pharmacokinetic profiles of nanomaterials in scientific reporting—a problem affecting the majoirty of of contemporary nanomaterials literature and innovative nanomaterials in early stages of preclinical development especially. Given the significant role of pharmacokinetic assessments to serve as guideposts for deciding whether to continue with the preclinical development and clinical translation of drug delivery systems, the prevalence of poor pharmacokinetic characterisations in nanomaterials research is particularly alarming. A conspicuous problem in many reports is the inappropriate selection of experimental designs and methodologies for studying nanomaterial pharmacokinetics, the consequences of which are increased uncertainty over the accurate interpretation of reported pharmacokinetic data and diminished experimental reproducibility throughout the field. Thus, there is renewed interest in the establishment of consistent and comprehensive strategies for designing preclinical experiments to assess the pharmacokinetics of nanomaterials with diverse physicochemical properties. Towards this end, herein are proposed simple guidelines for the experimental design of pharmacokinetic studies with nanomaterials drawn from the best research practices, principle strategies, and important considerations used in industry for collecting pharmacokinetic data in preclinical animal models. Specifically, key experimental design factors in these studies are identified and examined in the context of nanomaterials for optimality, including blood sampling strategy and technique, sample allocation and sampling time window, test species selection, experimental sources of pharmacokinetic variability, etc. Methods for noninvasive imaging-derived pharmacokinetic assessments of theranostic nanomaterials are also explored with particular focus on emission tomography imaging modalities. Taken together, this review will provide nanomaterial researchers with practical knowledge and pragmatic recommendations for selecting the best designs and methodologies for assessing the pharmacokinetic profiles of their nanomaterials, and hopefully maximise the chances of translational success of these innovative products into humans.

Systematic Review of Device Parameters and Design of Studies Bridging Biologic-Device Combination Products Using Prefilled Syringes and Autoinjectors.

Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA's Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. A systematic review on the device parameters and the PK comparability studies bridging the two presentations was conducted. Subsequently, whether device parameters or the PK study design may have influenced the PK comparability study results was evaluated. The reported device parameters for AI and PFS are generally consistent across BLAs, whereas the approach to assess PK comparability varied, including the study design. Most PK comparability studies met bioequivalence (BE) criteria. Upon inspection of the studies that did not meet BE criteria, injection depth of AI and the injection site for either AI or PFS were identified as potential influencing factors to the outcome of PK comparability study. This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination product development strategy, specifically design considerations for device and PK comparability studies.

Erythrocyte Ascorbate Is a Potential Indicator of Steady-State Plasma Ascorbate Concentrations in Healthy Non-Fasting Individuals.

Plasma vitamin C concentrations fluctuate in response to recent dietary intake; therefore levels are typically determined in the fasting state. Erythrocyte ascorbate concentrations have been shown to be similar to plasma levels, but little is known about the kinetics of ascorbate accumulation in these cells. In this study, we investigated ascorbate uptake into erythrocytes after dietary supplementation with vitamin C and compared it to changes in plasma ascorbate concentrations. Seven individuals with baseline fasting plasma vitamin C concentrations ≥ 50 µmol/L were depleted of vitamin C-containing foods and drinks for one week, and then supplemented with 250 mg vitamin C/day in addition to resuming their normal diet. Fasting or steady-state plasma ascorbate concentrations declined to almost half of their baseline concentration over the week of vitamin C depletion, and then returned to saturation within two days of beginning supplementation. Erythrocyte ascorbate concentrations exhibited a very similar profile to plasma levels, with values ~76% of plasma, and a strong linear correlation (r = 0.89, p < 0.0001). Using a pharmacokinetic study design in six individuals with baseline fasting plasma vitamin C concentrations ≥50 µmol/L, we also showed that, unlike plasma, which peaked between 2 and 4 h following ingestion of 200 mg of vitamin C, erythrocyte ascorbate concentrations did not change in the six hours after supplementation. The data from these two intervention studies indicate that erythrocyte ascorbate concentration provides a stable measure of steady-state plasma ascorbate status and could be used to monitor ascorbate status in healthy non-fasting individuals.

Physiologically based modelling of the pharmacokinetics of three beta-lactam antibiotics after intra-mammary administration in dairy cows.

Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.

Assessing the safety and pharmacokinetics of the monoclonal antibodies, VRC07-523LS and PGT121 in HIV negative women in South Africa: study protocol for the CAPRISA 012A randomised controlled phase I trial

IntroductionDespite extensive prevention campaigns and scale-up of antiretroviral therapy, HIV incidence among young women in southern Africa remains high. While the development of an efficacious vaccine remains a challenge, the...

Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?

Tacrolimus, a calcineurin inhibitor, is a common immunosuppressant prescribed after organ transplantation and has notable inter- and intrapatient pharmacokinetic variability. The sources of variability have been investigated using population pharmacokinetic modeling over the last 2 decades. This article provides an updated synopsis on published nonlinear mixed-effects analyses developed for tacrolimus in transplant recipients. The objectives were to establish a detailed overview of the current data and to investigate covariate relationships determined by the models. Sixty-three published analyses were reviewed, and data regarding the study design, modeling approach, and resulting findings were extracted and summarized. Most of the studies investigated tacrolimus pharmacokinetics in adult and pediatric renal and liver transplants after administration of the immediate-release formulation. Model structures largely depended on the study sampling strategy, with ∼50% of studies developing a 1-compartment model using trough concentrations and a 2-compartment model with delayed absorption from intensive sampling. The CYP3A5 genotype, as a covariate, consistently impacted tacrolimus clearance, and dosing adjustments were required to achieve similar drug exposure among patients. Numerous covariates were identified as sources of interindividual variability on tacrolimus pharmacokinetics with limited consistency across these studies, which may be the result of the study designs. Additional analyses are required to further evaluate the potential impact of these covariates and the clinical implementation of these models to guide tacrolimus dosing recommendations. This article may be useful for guiding the design of future population pharmacokinetic studies and provides recommendations for the selection of an existing optimal model to individualize tacrolimus therapy.

Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design.

Penicillins are widely used to treat infections in children; however, the evidence is continuing to evolve in defining the optimal dosing. Modern pediatric pharmacokinetic study protocols frequently favor opportunistic, "scavenged" sampling. This study aimed to develop a small-volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modeling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultrahigh-performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin, and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modeling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 h, remaining in the range of 98 to 103% of the original concentration. More-rapid analyte degradation had already occurred after 4 h, with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 h. Modeling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low-volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modeling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring.

Population pharmacokinetic modelling of rupatadine solution in 6-11 year olds and optimisation of the experimental design in younger children.

AimsTo optimise a pharmacokinetic (PK) study design of rupatadine for 2–5 year olds by using a population PK model developed with data from a study in 6–11 year olds. The design optimisation was driven by the need to avoid children’s discomfort in the study.MethodsPK data from 6–11 year olds with allergic rhinitis available from a previous study were used to construct a population PK model which we used in simulations to assess the dose to administer in a study in 2–5 year olds. In addition, an optimal design approach was used to determine the most appropriate number of sampling groups, sampling days, total samples and sampling times.ResultsA two-compartmental model with first-order absorption and elimination, with clearance dependent on weight adequately described the PK of rupatadine for 6–11 year olds. The dose selected for a trial in 2–5 year olds was 2.5 mg, as it provided a Cmax below the 3 ng/ml threshold. The optimal study design consisted of four groups of children (10 children each), a maximum sampling window of 2 hours in two clinic visits for drawing three samples on day 14 and one on day 28 coinciding with the final examination of the study.ConclusionsA PK study design was optimised in order to prioritise avoidance of discomfort for enrolled 2–5 year olds by taking only four blood samples from each child and minimising the length of hospital stays.

Exposure Matching for Extrapolation of Efficacy in Pediatric Drug Development.

During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.

Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design.

Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration (cervicovaginal fluid; CVF) or swab (rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized. Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50%-200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and rectal tissue biopsy over 48 hours. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r values were used to select the final predictive models. CVF exposure increased linearly with dose for all antiretrovirals (r(2) ≥ 0.23, P ≤ 0.02) except raltegravir (r(2) = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r(2) = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r(2) ≥ 0.37, rectal tissue (2)r ≥ 0.50, P ≤ 0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r(2) ≥ 0.81, P < 0.001). The same was noted for rectal tissue (r(2) ≥ 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r(2) = 0.91, P < 0.001). Mucosal fluids were positively correlated with tissue concentrations and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of tissue concentrations for these antiretrovirals.

Optimal design of perturbations for individual two-compartment pharmacokinetic analysis

ABSTRACTWe consider the optimal design of pharmacokinetic studies in patients that receive intermittent hemodialysis and intravenous antibiotic. Hemodialysis perturbs the pharmacokinetic system, providing additional opportunity for study. Designs that allocate measurements to occur exclusively during hemodialysis are shown to be viable alternatives to conventional designs, where all measurements occur outside of hemodialysis. Furthermore, hybrid designs with both conventional and intradialytic measurements have nearly double the efficiency of conventional designs. Convex optimal design and Monte Carlo techniques were used to simultaneously optimize hemodialysis event characteristics and sampling times, accounting for population pharmacokinetic heterogeneity. We also present several related methodological innovations.

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e.host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum aposteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of sophisticated systems pharmacology models and improved TCI tools are needed to accurately evaluate patients' exposure to drugs in general and to immunosuppressants in particular. Sequential studies, first without and then with TCI, should be conducted to validate the clinical benefit of TCI in homogenous populations; randomized trials are not feasible, because there are higher-priority research questions in alloHCT. In PartI of this article, we review the alloHCT process to facilitate optimal design of pharmacokinetic and pharmacodynamics studies. We also review the pharmacokinetics and TCI of calcineurin inhibitors and methotrexate.

Pharmacokinetic studies for proving bioequivalence of orally inhaled drug products-critical issues and concepts.

OPINION article Front. Pharmacol., 03 June 2015Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2015.00117

Special populations and pharmacogenetic issues in tuberculosis drug development and clinical research.

Special populations, including children and pregnant women, have been neglected in tuberculosis drug development. Patients in developing countries are inadequately represented in pharmacology research, and postmarketing pharmacovigilance activities tend to be rudimentary in these settings. There is an ethical imperative to generate evidence at an early stage to support optimal treatment in these populations and in populations with common comorbid conditions, such as diabetes and human immunodeficiency virus (HIV) infection. This article highlights the research needed to support equitable access to new antituberculosis regimens. Efficient and opportunistic pharmacokinetic study designs, typically using sparse sampling and population analysis methods, can facilitate optimal dose selection for children and pregnant women. Formulations suitable for children should be developed early and used in pharmacokinetic studies to guide dose selection. Drug-drug interactions between commonly coprescribed medications also need to be evaluated, and when these are significant, alternative approaches should be sought. A potent rifamycin-sparing regimen could revolutionize the treatment of adults and children requiring a protease inhibitor as part of antiretroviral treatment regimens for HIV infection. A sufficiently wide formulary of drugs should be developed for those with contraindications to the standard approaches. Because genetic variations may influence an individual's response to tuberculosis treatment, depending on the population being treated, it is important that samples be collected and stored for pharmacogenetic study in future clinical trials.