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The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use has published an addendum on estimands and sensitivity analysis in clinical trials along with related training materials. These define an estimand as a precise description of the treatment effect that reflects the scientific question of interest. In December 2022, the US Food and Drug Administration released draft guidance recommending estimands of interest be specified in bioequivalence trial protocols. However, experience in implementing estimands in clinical pharmacology trials is limited and so we introduce estimands and provide step-by-step considerations about the estimand thinking process in this setting. We also describe a particular case study, a bioequivalence trial, illustrating how the estimand framework can provide transparency and alignment throughout the design, conduct and analysis of the trial. This involves discussion of how to identify and handle intercurrent events, which are events that can affect interpretation of the drug or metabolite endpoints. Furthermore, we discuss the broader applicability of the estimand framework to other clinical pharmacology trials. Finally, we encourage further discussion between industry, academia, regulators and the International Council for Harmonisation on whether the estimand framework should be considered in all clinical pharmacology regulatory guidance documents., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The development of long-acting products of a characterized drug substance is of great interest. It is possible to support the development of these products with available clinical data by matching the exposure to a predefined bracket of a minimal concentration for efficacy and a maximal concentration for safety. This bracketing approach would cut down on the time and cost of new long-acting contraceptive products progressing to market. The current study describes the assessment of the data available to support a bracketing approach to conclude comparable levels of efficacy and safety for a postulated novel long-acting reversible contraceptive (LARC) product of levonorgestrel., Methods: Literature evidence of levonorgestrel efficacy, as quantified by the Pearl Index, was utilized and modeled by incorporating three LARC products for the estimation of a minimal concentration required for efficacy. Further literature was reviewed to quantify the maximal concentration required to ensure product safety. Additionally, a review of the regulatory precedence for the approach was conducted using European and UK databases., Results: There was a reasonable definition of the minimal concentrations for efficacy where the target concentrations of levonorgestrel were in the range of 200-400 pg/mL. Maximum concentrations for safety were less well defined. Although regulatory guidance supports the bracketing approach, there is little precedence for licensing new products based on pharmacokinetic data only, despite much reduced clinical and non-clinical packages being evidenced., Conclusions: Understanding of the exposure response is not currently considered sufficient to support a bracketing approach for a new levonorgestrel product. If additional safety data are established, current regulations may allow for a reduced application package. Additional work is needed to support the approach, and this could utilize the wealth of information in real-world datasets combined with systems models.

Introduction: A significant proportion of mothers take medication during the breastfeeding period, however knowledge of infant safety during continued breastfeeding is often limited. Breastmilk exhibits significant physiological heterogeneity, with a range of milk fat (creamatocrit), protein and pH values available within the literature. Mathematical models for the prediction of infant exposure are available and these predict that variable milk physiology will significantly affect accumulation of drugs within the breastmilk. These models are typically validated against limited datasets only, and to the best of our knowledge no widescale review has been conducted which accounts for the heterogeneity of breastmilk., Methods: Observed area under the curve milk-to-plasma (M/P) ratios and physicochemical properties were collected for a diverse range of drugs. The reliability of previously published mathematical models was assessed by varying milk pH and creamatocrit across the physiological range. Subsequently, alternative methods for predicting lipid and protein binding within the milk, and the effect of ionisation and physicochemical properties were investigated., Results: Existing models mis-predicted >40% of medications (Phase Distribution model), exhibited extreme sensitivity to milk pH (Log-Transformed model) or exhibited limited sensitivity to changes in creamatocrit (LogP o:w model). Alternative methods of predicting distribution into milk lipids moderately improved predictions, however altering the way in which milk protein binding was predicted and the effect of ionisation on this demonstrated little effect. Many drugs were predicted to have a significant range of M/P ratios., Discussion: These data show that consideration of the biological heterogeneity of breastmilk is important for model development and highlight that increased understanding of the physiological mechanisms underlying distribution within the milk may be essential to continue improving in silico methodologies to support infant and maternal health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Heo, Butler, Stamouli Simoncioni, Moult, Malamatari, Kerwash and Cole.)

Due to limited non-clinical and clinical data, European guidance recommends to discontinue breastfeeding when taking albendazole. The aim of this study was to consider the use of PBPK modeling to support the expected exposure in breastfed infants. A fully mechanistic PBPK approach was used to provide quantitative predictions of albendazole and its main active metabolite, albendazole sulfoxide, concentrations in plasma and breast milk of lactating women. The model predicted the exposure in adults and the large food effect, however, it does not predict all the clinical data for the exposure in children. Milk/plasma ratio predictions were also largely over-predicted for this lipophilic compound, but not for the less lipophilic metabolite. Predictions using the observed ratio and a worse-case exposure based on C max predictions, suggest doses to children through milk will be low. However, more clinical data are required before full exposure predictions can be made to breastfed infants., (© 2024 Crown copyright. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.)

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are hereditary haemoglobinopathies characterized by a reduction in functional β-globin chains. Both conditions cause tiredness and increase susceptibility to infection, which can lead organ failure, significantly reducing life expectancy and typically requiring those affected to undergo regular erythrocyte transfusion. Recently, a novel therapeutic treatment for SCD and TDT was approved by the UK regulatory body (Medicines and Healthcare products Regulatory Agency; MHRA). Exagamglogene autotemcel (Casgevy) is the first licensed therapy globally to utilize CRIPSR/Cas9 technology and induces an increase in expression of γ-globin chains to compensate for the reduction in functional β-globin. Casgevy represents a first-in-class therapeutic, and numerous considerations were made by the MHRA throughout its assessment of the medicine. These include, but are not limited to, the risk of tumorigenicity and off-target editing, a limited cohort size, the validity of proposed dosing and the conduction of only single-arm studies. The MHRA's analyses of the data to support the proposed indications are presented and discussed throughout this manuscript. Overall, the sponsors claims were considered well supported by their data, and Casgevy was licensed for the treatment of TDT or SCD in patients 12 years of age and older for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen-matched related HSC donor is not available.

Casgevy (exa-cel) is an autologous cellular therapy modified ex vivo by a CRISPR-Cas9-mediated gene-editing technology. For Casgevy to be granted the indication in transfusion-dependent β-thalassemia, one single-arm trial was submitted which was not amenable to conventional statistical analysis of 'effect of cause'. Therefore, an analysis was conducted on the basis of 'cause of effect' making use of the scheme described by Toulmin coupled to an analysis of causal inference. Based on the current data within the submitted study: subjects with transfusion-dependent β-thalassemia no longer needed a red blood cell transfusion with a 93-percent probability if and only if administered Casgevy; PNS = 93%. It is acknowledged that unknown elements of safety may yet be revealed by long-term follow-up of recipients of Casgevy. Its durability of efficacy is, at present, also an unknown that may also be ascertained by long-term follow-up of recipients. The limitations of a causal analysis are related to assumptions of the proposed causal structure which may not capture the complexity of the real world. Overall, the claim that Casgevy is indicated to treat people with transfusion-dependent β-thalassemia is considered to be supported by the results of the submitted study; the benefit-risk evaluation of Casgevy is found to be positive.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Physiologically based pharmacokinetic (PBPK) models represent computational technology to characterize drug behavior within the context of detailed human physiology. Today, PBPK is routinely used in drug development and regulatory approval to support decisions on how a medicine can be used under certain clinical conditions. As such, PBPK has the potential to enhance medicine use for populations that are often under-served globally in drug development and clinical care, namely pediatric patients, pregnant and lactating women. To facilitate broader applications of PBPK for these populations, we joined force and organized five hands-on workshops primarily to non-modelers on the principles of PBPK and its potential applications in pediatric and obstetric pharmacology in 2021 and 2022. In this open letter, we report learning objectives and content of such workshops and to highlight the significant value of these educational efforts., Competing Interests: Competing interests: T.N.J. and K.R.Y. are employees of Certara UK Limited (Simcyp Division). The authors declared no competing interests for this work. All other authors declare that they have no conflict of interest., (Copyright: © 2023 Freriksen J et al.)

Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.

Physiologically based pharmacokinetic modeling could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations in which there is currently limited or no available clinical PK data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by hepatic clearance mechanisms. Models were evaluated for metoprolol, tacrolimus, clindamycin, ondansetron, phenytoin, caffeine, fluoxetine, clozapine, carbamazepine, metronidazole, and paracetamol. The hepatic metabolism through cytochrome P450 (CYP) contributes significantly to the elimination of these drugs, and available knowledge of CYP changes during pregnancy has been implemented in the existing pregnancy physiology models. In general, models were able to capture trends in exposure changes in pregnancy to some extent, but the magnitude of pharmacokinetic change for these hepatically cleared drugs was not captured in each case, nor were models always able to capture overall exposure in the populations. A thorough evaluation was hampered by the lack of clinical data for drugs cleared by a specific clearance pathway. The limited clinical data, as well as complex elimination pathways involving CYPs, uridine 5'-diphospho-glucuronosyltransferase and active transporter for many drugs, currently limit the confidence in the prospective use of the models. Pregnancy-related changes in uridine 5'-diphospho-glucuronosyltransferase and transport functions are emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is in progress. Filling this gap is expected to further enhance predictive performance of models and increase the confidence in predicting PK changes in pregnant women for hepatically cleared drugs., (© 2023 Crown copyright and The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.)

Pregnancy-related physiological changes can alter the absorption, distribution, metabolism and excretion of medicines which may affect the safety and efficacy of the medicines administered in pregnancy. Pharmacokinetic data can thus be instrumental in supporting dose adjustments required in this population. This review considers the availability of published pharmacokinetic data for over 200 medicines of interest for use in pregnancy in the UK, to identify whether sufficient data currently exists, in principle, for any medicine or group of medicines to support dose adjustments to maintain maternal health through pregnancy. Very limited data was found for many of the medicines of interest. Nevertheless, well documented, large changes of exposure for some drugs, where data is available, highlights the urgent need to collect more data of good quality to inform appropriate doses, when needed, in this population. In addition, clinical study methodology can have an impact on the usefulness of the data and key clinical design aspects are highlighted for consideration in future clinical study design., Competing Interests: PC was an employee of the MHRA at the time of the research study and manuscript writing. She is currently an employee of AstraZeneca UK Ltd. The authors declare that this study received funding from the Bill and Melinda Gates Foundation. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Coppola, Kerwash, Nooney, Omran and Cole.)

Physiologically based pharmacokinetic modeling (PBPK) could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations where there are currently no available clinical data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by the kidney. Models were evaluated for ceftazidime, cefuroxime, metformin, oseltamivir, and amoxicillin. Because the passive renal process contributes significantly to the renal elimination of these drugs and changes of the process during pregnancy have been implemented in existing pregnancy physiology models, simulations using these models can reasonably describe the pharmacokinetics of ceftazidime changes during pregnancy and appears to generally capture the changes in the other medicines; however, there are insufficient data on drugs solely passively cleared to fully qualify the models. In addition, in many cases, active transport processes are involved in a drug's renal clearance. Knowledge of changes in renal transport functions during pregnancy is emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is a work in progress. Filling this gap is expected to further enhance predictive performance of the models and increase the confidence in predicting pharmacokinetic changes in pregnant women for other renally cleared drugs., (© 2022 Crown copyright. The Journal of Clinical Pharmacology © 2022 American College of Clinical Pharmacology. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.)

Physiologically based pharmacokinetics (PBPK) modelling is widely used in medicine development and regulatory submissions. The lack of clinical pharmacokinetic data in pregnancy is widely acknowledged; therefore, one area of current interest is in the use of PBPK modelling to describe the potential impact of anatomical and physiological changes during pregnancy on the medicine's pharmacokinetics. PBPK modelling could possibly represent a predictive tool to support the medicine benefit-risk decision and inform dose adjustment in this population and also to investigate medicine levels in the foetus to support the risk assessment to the foetus. In the context of regulatory application, there are, however, a number of considerations around model evaluation, and this should be tailored to the model purpose, in order to inform the confidence in the model for the intended application. A number of gestational age-related physiological changes are expected to alter the pharmacokinetics of medicines during pregnancy, and there are uncertainties on some parameters; therefore, well-qualified models are needed to improve assurance in the model prediction before this approach can be used to inform with confidence high-impact decisions as part of regulatory submissions., Competing Interests: The authors are employees of the Medicines and Healthcare products Regulatory Agency, UK., (Crown Copyright © 2021 (Medicines and Healthcare products Regulatory Agency).)

The aim of this observational review was to review trends in deficiencies in clinical pharmacology dossiers by analysing the frequency and characteristics of major objections (MOs) related to clinical pharmacokinetics and dose-exposure-response (DER) relationships in assessment reports for medicinal products submitted in centralised procedures to the European Medicines Agency (EMA). Initial Assessor (Day 120) assessment reports between 2013 and 2018 were reviewed MOs and characterised with regards to ATC code, orphan status, legal basis and type of molecule, major objection topic and if scientific advice had been sought during development. 23% of the 551 identified Day 120 assessments contained at least one major objection related to clinical pharmacology. Most common topics identified were related to the pharmacokinetics in the target populations, analytical methods, dose-exposure-response relationships, absorption, distribution, metabolism, excretion, comparative bioavailability, and bioequivalence issues. The importance of a robust clinical PK dossier in the assessment of marketing authorisation applications was highlighted by the high frequency of major objections. This review should provide valuable insights to ensure that aspects of bioanalytical methods, comparative bioavailability, PK in the target population and DER relationships are thoroughly addressed in future marketing authorisation applications., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

The current EMA drug interaction guideline was published in 2012. This guideline gives important recommendations on the information required to elucidate the interaction potential of an investigational drug, both as effects of the investigational drug on the PK of other drugs and effects of other medicinal products on the PK of the investigational drug. Additional information on the use of PBPK modelling to inform drug interaction information, is also available in the guideline on the reporting of physiologically based modelling and simulation (2018). Some points of clarification on the drug interaction guideline, particularly in the area of enzyme induction screening, have been published as the EMA questions and answers (2014) and these points and further additional points, were proposed to be incorporated into a new update of the guideline, for which a concept paper was published in 2017. This update, which is still in progress, was to include new recommendations in line with relevant emerging scientific data (e.g. in the area of drug transporters). It is also intended to harmonise requirements on drug interactions with other Regulatory Agencies and this will be facilitated by the recently announced ICH initiative., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. All rights reserved.)

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated., (© AlphaMed Press 2019.)