Pharmacometrics, the mathematical approaches to describe the transfer of drug through different biological compartments, are essential tools in clinical pharmacology research. The ethical necessity to study drugs accurately in the populations where they are to be used is increasingly recognized. To maximise the value of clinical data, study design and analysis must be appropriate. Historically, many datasets have been sent from African countries to better-resourced settings for analysis, but in recent years it has been demonstrated that capacity can be built and sustained within low and middle-income countries (LMIC)3. We report the establishment of the Uganda Chapter of Pharmacometrics Africa, to share learning with other countries seeking to build similar capabilities.

A document by Ranjeeta Sinvhal. Click on the document to view its contents.

Novel Gonadotrophin Releasing Hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix, and linzagolix have assessed treatment efficacy for fibroid related heavy menstrual blood loss in comparison to placebo. Marketing authorization has already been granted by several agencies including those in Europe, the United Kingdom, and the United States. Prior to marketing authorization, the European Medicines Agency recommends that Phase III registration trails should assess treatment efficacy in a representative study population, assess relevant outcomes with a comparison to gold-standard alternative treatment options and that long-term safety data will adequately be collected. In this review, we demonstrate limitations in the trial data generated to date, namely a lack of generalizability due to the restricted population studied, the absence of any comparison to alternative treatment methods, and findings limited to specific subgroups of patients because of the type of outcomes assessed. Symptoms related to uterine fibroids adversely affect many women’s quality of life and effective medical treatments are lacking. However, despite the urgent need for effective treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness, and cost-effectiveness in a representative population compared with alternative treatment methods before introduction into mainstream clinical practice.

Health systems encourage switching from originators to biosimilars as biosimilars are more cost-effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re-establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380,000 on drug costs in 2021/22. Of patients who reverted to their original biologic, 85% improved short-term where the concern was tolerability, and 90% where it was efficacy. Patients remained on treatment for a prolonged period after reverting. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post-switch if appropriate.

Aim: Nirmatrelvir as a new 3CL protease inhibitor for treating COVID-19 drug of antiviral drug, the potential side effects have not yet been fully studied yet. The aim of this study was to identify potential risk of Nirmatrelvir by analyzing post-marketing safety data based on the largest publicly available worldwide pharmacovigilance database. Methods: We analyzed Nirmatrelvir adverse events to detect and characterize relevant safety signals based on the FDA Adverse Event Reporting System database in 2022. Case/non-case approach were used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for AEs with ≥4 counts. Results: Total of 26846 cases were included. Disease recurrence [ROR(95%CI)=413.2(395.6-431.59)], dysgeusia [ROR(95%CI)=110.84(106.04-115.85)], anosmia [ROR(95%CI)=15.21(12.76-18.11)], ageusia [ROR(95%CI)=9.80(8.50-11.3)] and urticaria [ROR(95%CI)=1.91(1.69-2.17)] were the main safety signals. In addition, abdominal pain upper and skin toxicity were two specific safety signals of Nirmatrelvir. In pregnant population, a significant increased ROR was found in life-threatening [ROR(95%CI)=5.12(1.38-19.00)]. Conclusion: We identified that disease recurrence, dysgeusia, abdominal pain upper and skin toxicity were the main and specific safety signals of Nirmatrelvir. Clinician and pharmacist should pay attention on these AEs. Notably, a potential risk of Nirmatrelvir in pregnant population should be alerted.

Aims: Mirvetuximab soravtansine is the first-in-class antibody-drug conjugate approved in November 2022 for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). Methods: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in three clinical studies, and the plasma drug concentrations were analyzed using a nonlinear mixed-effects modelling approach to estimate the PK parameters, inter-individual variabilities, and residual errors. Stepwise covariate modelling was performed to identify covariates. Results: We developed a semi-mechanistic population PK model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumor cells. The model adequately described the concentration-time profiles for the three analytes. Patient body weight, serum albumin, and age were identified as the major covariates. Exposures in patients with renal or hepatic impairment were estimated. The effect of inhibition of cytochrome P450 (CYP) 3A4 on drug exposures was also evaluated. Conclusions: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. The model also showed that dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

Abstract Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer patients incur an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, non-vitamin K oral anticoagulants (NOACs) are at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major drug-drug interactions have been identified as a reason to withhold NOACs and to rather choose an alternative. Furthermore, practical guidance on what constitutes a major interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with drug-drug interactions between NOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case. Key words: drug-drug interactions, anticoagulation, non-vitamin K oral anticoagulants, cancer, cancer associated thrombosis

The poly lactate co-glycolic acid (PLGA) nanoparticles of tubercular drugs have been demonstrated to have sustained release profile over seven days. There is no information on the location or mode of release of these nanoparticles in living system. Therefore, we have planned the study to explore the pharmacokinetics and biodistribution of PLGA rifampicin nanoparticles in healthy human volunteers. Rifampicin was labeled with 99mTc by indirect method and nanoparticles were prepared by a single emulsion evaporation method. To investigate the pharmacokinetics and biodistribution of nanoparticles, a single dose of 450 mg of rifampicin was administered orally to healthy human volunteers divided into two different groups. Following a single oral dosage of the rifampicin nanoformulation, the PK parameters were significantly different between the nanoparticle and conventional groups AUC (113.8 vs 58.6), MRT (16.2 vs 5.8) and Ke (0.04 vs 0.10). Also SPECT/CT images revealed bio-distrubution of nanoparticles in the distal portions of the intestine, which is consistent with our dosimetry analysis Significant difference in PK parameters and bio-distribution of nanoparticles in spleen and lymph nodes with maximum deposition were observed in large intestine. Nanoparticle distribution pattern may be advantageous for the treatment of intestinal or lymph node TB and has the potential to result in a lower dose of rifampicin nanoformulation for the treatment of pulmonary TB.

The field of pharmacometrics has been responsible for countless advancements within the drug development space. In recent years, we have witnessed the implementation of both new and revived analytical methods to increase clinical trial success and even supplement the need for clinical trials all together. Throughout this article we will explore the path of pharmacometrics from its inception to present day. At this point in time, the target of drug development has been the average patient, and population approaches have primarily been utilized to support just that. The challenge we are now facing involves the translation from treating the typical patient to treating the real-world patient. For this reason, it is our opinion that future development efforts should account more for the individual. With advanced pharmacometric methods and growing technological infrastructure, precision medicine can become a development priority rather than a clinician's burden.

Aim Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains the standard of care. CYP2C19 genetic polymorphisms results in variable Clopidogrel bioactivation. Increased function (CYP2C19*17) allele carriers (rapid metabolizers (RM) or ultrarapid metabolizers (UM)), are Clopidogrel hyper-responders and hence more susceptible to Clopidogrel related bleeding. Since current guidelines recommend against routine genotyping following PCI, data on the clinical utility of CYP2C19*17 genotype guided strategy are sparce. Our study provides real-world data on the 12-month follow-up of CYP2C19 genotyping in patients post-PCI. Methods This is a cohort study within an Irish population receiving 12 months of DAPT following PCI for ACS or CCS. It identifies the prevalence of CYP2C19 polymorphisms within an Irish population and describe the ischaemic and bleeding outcomes after 12 months of Clopidogrel DAPT. Results 129 patients were included with the following CYP2C19 polymorphism prevalence: 30.2% hyper-responders (26.4% RM (1*/17*), 3.9% UM (17*/17*)) and 28.7% poor-responders (22.5% IM (1*/2*), 3.9% IM (2*/17*), 2.3% PM (2*/2*)). Total bleeding incidence at 12-months increased from poor-responders (0.0%) to normal-responders (15.0%), to hyper-responders (25.0%). Compared to poor-responders, hyper-responders were significantly more likely to experience a bleeding event (25.0% vs 0.0%, P = 0.044). Conclusions The prevalence of CYP2C19 polymorphisms in Ireland is 58.9% (30.2% CYP2C19*17, 28.7% CYP2C19*2) with approximately 1 in 3 chance of being a Clopidogrel hyper-responder. The trend of increasing bleeding with increasing CYP2C19 activity, suggests a genotype guided strategy may have clinical utility identifying high-bleeding-risk with Clopidogrel in CYP2C19*17 carriers but further studies are required.

Introduction: Prazosin is an antihypertensive medication which can be used to help with post-traumatic stress disorder (PTSD) symptoms. Little data is currently available on its safety in pregnancy. Objective: To assess the fetal and pregnancy safety associated with Prazosin exposures in early Pregnancy. Methods: Subjects were 11 patients who took Prazosin during pregnancy and were counselled at the FRAME clinic in London Health Sciences Centre (Ontario, Canada) between January 1, 2000 to December 31, 2021. Data on their other exposures and pregnancy outcomes were collected from medical records and through telephone questionnaires. Results: It was found that 6 /11 (54.5%) subjects did not report any adverse outcomes and were uneventful pregnancies. There were 2 miscarriages. Birthweights were within the normal range for the remaining 9 pregnancies. Adverse events reported were consistent with background population expectation, including: 1 postpartum hemorrhage, 1 case of preeclampsia, 1 preterm birth, 2 NICU admissions, and 2 caesarean sections. Discussion / Conclusion: For these 11 subjects, pregnancy outcomes after exposure to Prazosin were consistent with typical outcomes from unexposed pregnancies. More data are needed to conclude that Prazosin is safe for use in pregnant subjects. However, the lack of adverse effects above baseline is reassuring to future patients who may be unintentionally exposed to Prazosin while pregnant. Therefore, this study contributes valuable data toward monitoring safety of Prazosin in Pregnancy.

Over the last three to four decades, Therapeutic Drug Monitoring (TDM) has shaped itself as therapeutic drug management (TDM), an integral component of precision medicine. The practice of TDM is not extensive in India, despite being one of the fastest growing economies in the world. It is currently limited to a few academic medical centers and teaching hospitals. Apart from the immunosuppressive drugs, several other therapeutic areas like anticancer, antifungals, antibiotics and antitubercular have demonstrated great potential to improve the patient outcomes in the Indian settings. Factors like higher prevalence of nutritional deficiencies, tropical diseases, widespread use of alternative medicines, unalike pharmacogenomics, and sparse population specific data available on therapeutic ranges of several drugs, makes in the population of this subcontinent unique regarding the relevance of TDM. Despite the impact of TDM in clinical science and it’s widespread application, TDM has failed to receive the attention it deserves in India. This review intends to bring out a strength-weakness-opportunity and threats (SWOT) analysis for TDM in India so that appropriate steps for fostering growth of TDM could be envisioned. The need of the hour is creation of a cooperative group including all the stake holders like TDM professionals, clinicians and the government and devising a National Action Plan to strengthen TDM. Nodal TDM centres should be established and pilot programs should be rolled out for identifying the thrust areas for TDM in the country, capacity building and creating awareness to integrate TDM into mainstream clinical medicine.

Abstract Objective To compare the gestational age of neonates in utero exposed to benzodiazepines (BDZs) with none exposed controls. Secondary objectives were; birth weight, presence of congenital malformations, APGAR score, and the need for > 3 months (prolonged) maternal psychiatric care. Study design A retrospective cohort study of women and neonates from 2013 to 2021 with univariate and multivariable analysis to study the associations between BDZs exposure and gestational age compared to non-exposed women with mental health problems. Results We found that BDZ exposure was associated with a lower gestational age of -3.2 days (95% CI -5.8 , -0.53 days). Women in the exposed group had an increased risk of psychiatric care (adjusted OR 2.511 (95% CI 1.675 – 3.782), p < 0.001). Conclusion We found that in utero BDZ exposure was independently associated with a significantly lower gestational age of the neonates and prolonged psychiatric care of their mothers.

● Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. ● Implementation of testing into routine practice across a healthcare system requires consideration of the evidence, clinical utility, cost-effectiveness, and operational requirements. ● A national approach to providing pharmacogenomic test recommendations and centralised commissioning will reduce inequity and duplication, but must be transparent and evidence based

A document by Emma Magavern. Click on the document to view its contents.

The emerging issue of rising gabapentinoid misuse is being recognised alongside the lack of current evidence supporting the safe and effective deprescribing of gabapentinoids. This scoping review aimed to assess the extent and nature of gabapentinoid deprescribing interventions in adults, either in reducing dosages, or prescribing of, gabapentinoids. Electronic databases were searched on 23rd February 2022 without restrictions. Eligible studies included randomised, non-randomised and observational studies that assessed an intervention aimed at reducing/ceasing the prescription/use of a gabapentinoid in adults for any indication in a clinical setting. The research outcomes investigated type of intervention, prescribing rates, cessations, patient outcomes, and adverse events. Extracted outcome data was categorised as either short (≤ 3 months), intermediate (>3 but <12 months) or long (≥ 12 months) term. A narrative synthesis was conducted. The four included studies were conducted in primary and acute care settings. Intervention were of dose reducing protocols, education and/or pharmacological-based approaches. In the randomised trials, gabapentinoid use could be ceased in at least one-third of participants. In the two observational trials, gabapentinoid prescribing rates decreased by 9%. Serious adverse events and adverse events specifically related to gabapentinoids were reported in one trial. No study included patient-focussed psychological interventions in the deprescribing process, nor provided any long-term follow-up. This review highlights the lack of existing evidence in this area. Due to limited available data, our review was unable to make any firm judgements on the most effective gabapentinoid deprescribing interventions in adults, highlighting the need for more research in this area.

Aim: Develop PBPK models of semaglutide to estimate the pharmacokinetic profile for subcutaneous (SC) injections in children and adolescents with healthy and obese body weights. Methods: Pharmacokinetic modeling and simulations of semaglutide SC injections were performed using the Transdermal Compartmental Absorption & Transit (TCAT™) model implemented in GastroPlus™ v.9.5 modules. A PBPK model of semaglutide was developed and verified in the adult population, by comparing the simulated plasma exposure with the observed data, and further scaled to the pediatric populations with normal and obese body weight. Results: The Semaglutide PBPK model was successfully developed in adults and scaled to the pediatric population. Our P-PBPK simulations indicated a significant increase in Cmax values for the 10-14 years pediatric population with healthy body weights, which was higher than the observed values in adults at the reference dose. Since gastrointestinal adverse events are related to increased semaglutide exposure, peak concentrations outside the target range may represent a safety risk for this pediatric age group. Besides, PBPK models indicated that body weight was inversely related to semaglutide exposure in children and adolescents, which is in line with the results observed in population pharmacokinetic studies in adults. Conclusion: Due to the absence of semaglutide pharmacokinetic data for the pediatric population, these PBPK models will aid in the development of dosing regimens and sampling times. Thus, increasing the efficiency of future pediatric clinical trial studies which can be replaced or improved by PBPK models.

A 53-year-old woman with a history of acute myeloid leukemia received a second allogenic hematopoietic stem cell transplant (HSCT) and was prescribed, among other medications, acyclovir and letermovir (480 mg daily oral dose) for prophylaxis of respectively herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit (ICU) for dyspnea and oliguria. Laboratory investigations revealed acute kidney injury, but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma suspected a mitochondrial toxicity. Letermovir therapy was interrupted and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (40.7 h) that was not significantly influenced by continuous venovenous hemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted non-functional OATP1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.