Commentary: Animal free applications in the development of cell-based therapies

Aims: Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing of propofol in this population. Methods: A non-linear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants. Results: 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from three studies. Body weight (BW) of the pooled study population was 3.050 (0.580 – 11.440) kg, postmenstrual age (PMA) was 36.56 (27.00 – 43.00) weeks and postnatal age (PNA) was 1.14 (0 – 104.00) weeks (median and range). A three compartment structural model was identified and the effect of BW was modeled using fixed allometric exponents. Elimination clearance maturation was modeled accounting for the maturational effect on elimination clearance until birth (by GA) and postpartum (by PNA/GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.63 L min-1) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume (V1) in function of PNA improved the model fit. Conclusions: It is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio-anatomical changes may explain the changes in V1. The developed model may serve as a prior for propofol dose finding in (preterm) neonates.

AIM: The main objective was to determine the prevalence of prescribing issues in HIV-infected subjects ≥65 years according to the Beers and STOPP/START criteria and drug-drug interactions (Liverpool website). Secondary objectives were to assess the concordance between Beers and STOPP/START criteria in our population, and to identify the drugs most frequently involved in the prescribing issues. METHODS: Cross-sectional cohort study based on a systematic review of the electronic drug prescriptions of 91 HIV-infected patients aged ≥65 years. Discrepancies between prescription criteria were assessed using crosstabs and compared using the Chi-square test or Fisher exact test. RESULTS: The mean age was 72.1 (5.6) years, 75.8% had ≥3 comorbidities, and 59.3% polypharmacy. Prescribing issues were identified in 87.9%; 71.4% by STOPP/START and 45.1% by Beers. Comparing both criteria, 56.9% of prescribing issues by STOPP/START were detected by Beers, while 92.5% of those detected by the Beers criteria were detected by STOPP/START (p<0.001). Orange/red flag interactions were found in 45.1%: 3 severe (red) in 2 patients (2.2%). The most frequent drugs involved in prescribing issues were benzodiazepines (>30%). Cobicistat was the drug most frequently involved in interactions (42.9%). CONCLUSIONS: The prevalence of prescribing issues among older HIV-infected persons gives cause for concern, as it is almost 90%. Optimization strategies, including a critical review of the treatment plan, should be implemented in clinical routine by a multidisciplinary team, in particular in patients with multiple comorbidities and polypharmacy. The STOPP/START criteria should be recommended for European populations, since they seem to better detect prescribing issues.

Aims: The investigation regarding the clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is rare. This study evaluated safety and efficacy of PD-1 with Toripalimab, Camrelizumab or Sintilimab for Chinese Hepatocellular carcinoma (HCC) patients in a real-life cohort. Methods: We retrospectively analyzed HBV associated HCC patients treated with Toripalimab, Camrelizumab or Sintilimab in a retrospective cohort from Nov 2018 to Dec 2019. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP) and overall survival (OS). Results: Seventy eight patients were finally included in the analysis: 26 for Toripalimab, 36 for Camrelizumab, and 16 for Sintilimab. Mean duration of follow-up was 22.7 ± 12.6 weeks and the mean Cycles of PD-1 at cut-off were 4.8 ± 2.7 for all patients. The ORR and DCR for the whole cohort were 17.9% and 73.1%, respectively. Overall, 21 (26.9%) patients had radiological disease progression and 6 (7.7%) patients died during follow-up. Median PFS was 40.7 (95% CI, 34.7-46.7) weeks, median TTP was 45.7 (95% CI, 40.5-60.0) weeks, and median OS was 51.1 (95% CI, 46.4-55.9) weeks. Most frequent drug-related AEs were Rash (19.2%), Hypertension (15.4%), Fatigue (12.8%), Paraesthesia (12.8%), and Diarrhoea (10.3%). Conclusions: Our findings suggest that: 1. PD-1-targeted immunotherapy with Toripalimab, Camrelizumab or Sintilimab yielded a promising outcome in Chinese HBV patients with HCC; 2. Immunotherapy was well tolerated generally and had manageable side effects, which is worth of popularization and application in clinical practice.

Aims This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised dosing regimen for patients with liver dysfunction. Methods The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic (ROC) curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by TBIL (TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed. Results ROC curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance (CL), the volume of distribution (V) and oral bioavailability (F) were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole CL was significantly associated with total bilirubin (TBIL) and platelet count. The V increased with weight. Patients with TBIL-1 could be treated with loading dose of 400 mg every 12 hours (q12h) for first day and maintenance dose of 100 mg q12h intravenously or orally. TBIL-2 and TBIL-3 patients could be treated with loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily (qd) and 50 mg qd orally or intravenously, respectively. Conclusions TBIL-based dosing regimens provide a practical strategy for voriconazole maximizing treatment outcomes.

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug-target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended provide a guide to modellers in their model endeavours to simplify these complicated models.

Drug therapy in pregnancy may cause anxiety to both physicians and patients due to uncertainty regarding dosing and safety. Nevertheless, the need for medication is high given that maternal chronic illnesses such as hypertension or diabetes are on the rise1. In a national study in the United States over 33 years, the prevalence of prescription medication use by pregnant women in the first trimester increased by 62.5% between the first 2 years of the study and the last 2 years2. Furthermore, the average number of medications used anytime in pregnancy has increased two-fold 2. More recent research from different countries has found that medications are widely used in pregnancy, with the prevalence of using at least one drug ranging from 60 to 90 percent, excluding vitamins and minerals 3-5. Prescription of drugs with potential teratogenicity has also increased in pregnancy, including folate antagonists or angiotensin converting enzyme inhibitors3,4. This suggests that many women go into pregnancy with chronic conditions that require medications, including those may pose some degrees of risk to the fetus, since the maternal benefit may outweigh the risk or if the pregnancy is unplanned. Successful treatment of pregnant patients requires a correct diagnosis and providing treatment that not only is effective but also balances risks and benefits, as maternal health is the best defense for fetal health. However, concomitant health conditions, and the intrinsic complex physiological changes associated to pregnancy can make prescribing in this population a particularly challenging balancing act. Very few drugs have specific pregnancy dosing regimens supported by scientific evidence in spite of well-known pharmacokinetics changes during pregnancy affecting a large proportion of medications (Table 1)6-10. Data on drug efficacy and safety is sorely lacking for pregnant women, even for drugs that have been available for decades. Pregnant patients are commonly excluded from clinical trials during the drug development process due to ethical and safety concerns, which implies that the majority of drug therapy data in pregnancy have been extrapolated from males and to a much lesser extent, from non-pregnant females11. However, using extrapolated data in pregnancy has a number of major drawbacks such as that the extrapolation commonly fails to account for the changes in drug metabolism related to pregnancy 6. Multiple physiological changes in pregnancy, including those affecting pharmacokinetics, must be considered when prescribing. Furthermore, these changes can also be affected by genetic variability10. Some drugs need to be used at higher doses in pregnancy due to increasing metabolic demand. A classic example is thyroid hormone, which requires a 30 to 45 percent higher dose in order to maintain euthyroid state due to limited compensation in pregnant patients with underlying thyroid disease 12. One of the biggest physiologic changes in pregnancy is the expansion of plasma volume by approximately 50 percent due to hormone-mediated vasodilation, leading to activation of the renin-angiotensin-aldosterone system10. This change results in and increased volume of distribution for hydrophilic drugs and reduced peak concentrations 6. Increased glomerular filtration rate in pregnancy also increases elimination of renally cleared drugs; a classic example of this effect is lithium13. Changes in hepatic enzyme activity in pregnancy, including upregulation of cytochrome P450 and glucuronidation, are another cause of increased metabolism and elimination of drugs14. Increased metabolism of lamotrigine by glucuronidation results in low drug levels in pregnancy and this can be further affected by polymorphism of UDP-glucuronosyltransferases 15. One strategy to address changes in drug metabolism is to use therapeutic drug monitoring (TDM) with blood levels; however, TDM analysis is not readily available for the majority of drugs used in pregnancy, limiting the usefulness of this strategy in clinical practice. Furthermore, lower total drug levels do not necessarily translate to less free drug due to volume expansion in pregnancy leading to relative hypoalbuminemia 6. For some drugs, many clinicians modify the dosing regimen on their own based on limited pharmacokinetic data. For example, labelatol, a common antihypertensive used in pregnancy, has a half-life of only 1.7 ± 0.27 hours in patients in the 3rd trimester of pregnancy, compared to 6-8 hours outside of pregnancy16. This difference leads many clinicians to prescribe labelatol three times per day based on patient response instead of twice-per-day as per drug monograph16. However, there is considerable variation among clinicians due to lack of scientific evidence. For example, in patients diagnosed with acute pulmonary embolism, twice-per-day dosing and once-per-day dosing of low molecular weight heparin are both commonly used 17. Enoxaparin once-per-day versus twice-per-day in a population pharmacokinetics study both achieved target plasma concentration in pregnancy18; however, once daily regimen has not been universally adopted in clinical practice and no similar data are available for other low molecular weight heparins. Pregnancy is also a vulnerable period for the occurrence of cardiac events. In particular consideration must be given to patients known to have long QT syndrome or on QT prolonging drugs. The adrenergic nature of labor and delivery may lead to catecholaminergic polymorphic ventricular tachycardia in these patients. Furthermore, patients with congenital long QT syndrome are also at risk during a nine-month post-partum period 19. Treatment with beta-blockers are the mainstay of therapy during pregnancy and in the post-partum period19. There is a lack of data for therapeutics that may be urgently needed intrapartum that may prolong the QT interval in susceptible patients. For example, oxytocin and carbetocin are both known to prolong the QT interval but may be required for prevention or treatment of postpartum hemorrhage20,21. Clinical guidelines for using oxytocin for augmentation or induction of labour are lacking and some obstetricians may choose to do an elective Caesarian section to avoid prolonged oxytocin in these patients although this is not evidence based due to lack of studies. In addition to the challenges in proper prescribing in pregnancy, the information on teratogenicity of drugs is also limited. Management of the care of a pregnant patient must balance the benefits of treating the maternal medical condition with possible adverse effects on the fetus. Clinicians must rely on animal data, data from pregnancy registries, and published case control studies and case reports to make these risk/benefit assessments. These resources are by no means ideal as results are confounded by recall bias, selection bias, and inconsistency, as well as lack of ability to extrapolate safety between species 22. Other than a few specific drugs with clear evidence of harm, many drugs have limited information, leading to variable practice among clinicians and inconsistent information provided to patients. For example, while angiotensin-converting enzyme inhibitor induced fetopathy has been described since the 1990s and accepted by medical community consistently23, the risk of maternal corticosteroid use with increased risk of cleft lip and palate has not been consistent among studies24,25. In addition, long term corticosteroid use is also linked to increased risk of preeclampsia which needs to be taken into consideration for treatment and monitoring26. The US Food and Drug Administration recognized the limitation of the prior FDA classifications for medication use in pregnancy (A, B, C, D, X category system). Thus, the “Pregnancy and Lactation Labeling Rule” went into effect by the FDA in June 2015, requesting manufacturers to provide available information regarding risks in pregnancy and lactation in a narrative summary; however, according to a recent survey, less than 50 percent of prescribers were aware of this change, while more than half deemed the narrative summary not helpful 27. Lack of quality data is one of the barriers identified in this survey. In addition to the rating systems used in various jurisdictions, an evidence-based medicine classification system has been developed by toxicologists, which can be used to assist clinical decision making. Unfortunately, all of the currently available systems are of limited utility due to reliance on small studies and inability to be updated frequently with new data22. Since the thalidomide story in the 1960s, much advancement has been made in medical therapy in pregnant women. However there remains a significant knowledge gap in pharmacological information which may expose patients to either toxicity or under treatment with reduced efficacy. In addition, numerous commonly used medications lack concrete data on teratogenicity. Supported by the NIH, the Pediatric Trials Network is currently conducting a multicentre trial studying the pharmacokinetics and safety of commonly used drugs in lactating women and breastfeeding infants in North America (NCT03511118); similar studies in pregnancy are also warranted to guide appropriate dosing. Long term data on children with fetal exposure for developmental toxicity are also urgently needed, and while some data for newer medications is systematically collected by international registries, in general information on fetal risks of maternal exposures is limited to incidental data obtained from accidental exposures. Finally, making all up-to-date information readily available to clinicians should also be a priority. References1. Sun AJ, Li S, Zhang CA, Jensen TK, Lindahl-Jacobsen R, Eisenberg ML. Parental comorbidity and medication use in the USA: a panel study of 785 000 live births. Hum Reprod.Mar 18 2020.2. Mitchell AA, Gilboa SM, Werler MM, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. American journal of obstetrics and gynecology. Jul 2011;205(1):51 e51-58.3. Ventura M, Maraschini A, D’Aloja P, et al. Drug prescribing during pregnancy in a central region of Italy, 2008-2012. BMC Public Health. May 15 2018;18(1):623.4. Engeland A, Bjorge T, Klungsoyr K, Hjellvik V, Skurtveit S, Furu K. Trends in prescription drug use during pregnancy and postpartum in Norway, 2005 to 2015.Pharmacoepidemiology and drug safety. Sep 2018;27(9):995-1004.5. Lutz BH, Miranda VIA, Silveira MPT, et al. Medication Use among Pregnant Women from the 2015 Pelotas (Brazil) Birth Cohort Study. International journal of environmental research and public health. Feb 5 2020;17(3).6. Koren G, Pariente G. Pregnancy- Associated Changes in Pharmacokinetics and their Clinical Implications.Pharmaceutical research. Feb 12 2018;35(3):61.7. Yerby MS, Friel PN, McCormick K, et al. Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding. Epilepsy research. Apr 1990;5(3):223-228.8. Prevost RR, Akl SA, Whybrew WD, Sibai BM. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy. 1992;12(3):174-177.9. Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis. Sep 1977;136(3):370-376.10. Blackburn S. Chapter 9. Cardiovascular System. Maternal, Fetal, & Neonatal Physiology . 5th ed. London, United Kingdom: Elsevier; 2018:251-259.11. Huybrechts KF, Bateman BT, Hernandez-Diaz S. Use of real-world evidence from healthcare utilization data to evaluate drug safety during pregnancy.Pharmacoepidemiology and drug safety. Jul 2019;28(7):906-922.12. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. Mar 2017;27(3):315-389.13. Wesseloo R, Wierdsma AI, van Kamp IL, et al. Lithium dosing strategies during pregnancy and the postpartum period. The British journal of psychiatry : the journal of mental science. Jul 2017;211(1):31-36.14. Betcher HK, George AL, Jr. Pharmacogenomics in pregnancy. Seminars in perinatology. Jan 25 2020:151222.15. Milosheska D, Lorber B, Vovk T, Kastelic M, Dolzan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. British journal of clinical pharmacology. Aug 2016;82(2):399-411.16. Rogers RC, Sibai BM, Whybrew WD. Labetalol pharmacokinetics in pregnancy-induced hypertension.American journal of obstetrics and gynecology. Feb 1990;162(2):362-366.17. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood advances. Nov 27 2018;2(22):3317-3359.18. Patel JP, Green B, Patel RK, Marsh MS, Davies JG, Arya R. Population pharmacokinetics of enoxaparin during the antenatal period. Circulation. Sep 24 2013;128(13):1462-1469.19. Garg L, Garg J, Krishnamoorthy P, et al. Influence of Pregnancy in Patients With Congenital Long QT Syndrome. Cardiology in review. Jul/Aug 2017;25(4):197-201.20. Clunies-Ross N, Roston TM, Taylor J, et al. The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial. Anesthesia and analgesia. Mar 5 2020.21. Liou SC, Chen C, Wong SY, Wong KM. Ventricular tachycardia after oxytocin injection in patients with prolonged Q-T interval syndrome–report of two cases. Acta anaesthesiologica Sinica. Mar 1998;36(1):49-52.22. Wilmer E, Chai S, Kroumpouzos G. Drug safety: Pregnancy rating classifications and controversies.Clinics in dermatology. May-Jun 2016;34(3):401-409.23. Barr M, Jr., Cohen MM, Jr. ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection.Teratology. Nov 1991;44(5):485-495.24. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies.American journal of medical genetics. Sep 17 1999;86(3):242-244.25. Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology. Nov 1997;56(5):335-340.26. Cai E, Czuzoj-Shulman N, Abenhaim HA. Maternal and fetal outcomes in pregnancies with long-term corticosteroid use. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. Aug 20 2019:1-8.27. Namazy J, Chambers C, Sahin L, et al. Clinicians’ Perspective of The New Pregnancy and Lactation Labeling Final Rule (PLLR): Results from an AAAAI/FDA Survey. The journal of allergy and clinical immunology. In practice. Feb 18 2020.

In a recent issue of Br J Clin Pharmacol Smith et al1 published an outstanding commentary titled ‘Dosing will be a key success factor in repurposing antivirals for Covid-19’. They highlighted that the success in our repurposing efforts will be dependent on ‘getting the dose right’ for drugs which have been developed for different indications and stressed some of the unique challenges of treating this particular disease. They pointed the reader to lopinavir/ritonavir (LPV/r) as an example of a repurposed antiviral and the limited experience of this drug regimen (and other treatments) in the elderly population with comorbidities – ie those most at risk from Covid-19. It is on the issue of comorbidities, polypharmacy and drug-drug interactions (DDIs) that we wish to comment.

Drug disposition in children is impacted by developmental changes in drug absorption, distribution, metabolism and excretion. This mandates the need for dosing regimens specifically tailored to children. Yet, there are gaps in the knowledge on these developmental changes, for example regarding hepatic and renal drug transport and drug metabolism, putting children at risk for subtherapeutic or toxic drug exposure. Pediatric drug research is faced with ethical and analytical challenges. This review addresses how these knowledge gaps can be filled and challenges can be overcome by using innovative study designs.

Hundreds of researchers are working to develop a vaccine and are evaluating drugs to mitigate the adverse health and economic consequences of COVID-19 (Coronavirus disease 19) worldwide. If novel compounds are found, geopolitical and economic variables will determine their introduction to communities. Therefore, finding low-cost and widely accessible drugs for prevention or treatment of COVID-19 would be ideal.A recent study found that ivermectin, an FDA-approved anti-parasitic drug, has inhibitory effects on replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Ivermectin has broad anti-viral activity through inhibition of viral proteins including importin α/β1 heterodimer and integrase protein2. Caly and colleagues reported that the addition of ivermectin at a concentration of 5 micromolar (μM) (twice the reported IC50) to Vero-hSLAM cells, 2 hours post infection with SARS-CoV-2, resulted in a reduction in the viral RNA load by 99.98% at 48 hours1. The authors suggested that this drug could reduce the viral load in infected patients, with potential effect on disease progression and spread.While the findings by Caly and colleagues provide some promise, there is no evidence that the 5 μM concentration of ivermectin used by Caly and colleagues in their in vitro SARS-CoV-2 experiment, can be achieved in vivo . The pharmacokinetics of ivermectin in humans is well described (Figure 1)3-5, and even with the highest reported dose of approximately 1700 µg/kg (i.e. 8.5 times the FDA-approved dose of 200 μg/kg), the maximum plasma concentration was only 0.28 µM5. This is 18 times lower than the concentration required to reduce viral replication of SARS-CoV-2in vitro . Ivermectin accumulation in tissues is mild and would not be sufficient to achieve the antiviral effect with conventional doses6. Although high doses of ivermectin in adults or children are well tolerated5,7, the clinical effects of ivermectin at a concentration of 5 μM range are unknown and may be associated with toxicity. Consequently, ivermectin has in vitroactivity against SARS-CoV-2 but this effect is unlikely to be observedin vivo using current dosing.Amidst fear of the pandemic, the public and some physicians are now using ivermectin off-label for prophylaxis or as adjuvant therapy for COVID-19. Because ivermectin is only commercially available as a 3 or 6 mg tablets or a 6 mg/ml oral suspension, in order to administer a high dose, some people may experiment with more concentrated veterinary formulations. These actions are not based on clinical trials and have motivated cautionary statements from institutions such as the FDA against the use of pharmaceutical formulations of ivermectin intended for animals as therapeutics in humans 8.Potential avenues for further investigation into repurposing ivermectin for SARS-CoV-2 may be to: (i) develop an inhaled formulation to efficiently deliver a high local concentration in the lung, whilst minimizing systemic exposure; and (ii) evaluate more potent ivermectin analogs (e.g. doramectin) which may also inhibit SARS-CoV-2. These are areas for research – clearly, further studies are needed before ivermectin can be used for the prevention and treatment of COVID-19. As recently discussed in BJCP, this highlights the critical need to consider pharmacological principles to guide in vitro testing when repurposing old drugs for therapeutic use against COVID-199.

Aim: Infantile haemangioma (IH) is the most common benign tumour in children. Since 2014, propranolol has become the first-choice therapy and currently Hemangiol® is the only approved drug for complicated haemangioma. This post-marketing study reported the use of Hemangiol® for IH in paediatric practice. Method and Results: From January 2014 to November 2018, 94 children (median age 4 [0;21] months; 75% female) treated with Hemangiol® for proliferative IH were enrolled in the study. The systematic paediatric cardiology consultation never contraindicated beta-blockers. Two Hemangiol® initiation protocols were used: a conventional ambulatory 3-week titration phase protocol (N=76, 80.9%), and a rapid initiation protocol with a 48-hour dose escalation in conventional hospitalization for severe proliferative IH (N=18, 19.1%). In both protocols, the haemodynamic tolerance was good. The mean maintenance dose of Hemangiol® was 2.7±0.8 mg/kg/day, with a median treatment duration of 7 [1.5;19] months. Adverse events (AEs) have been found in 25 (26,6%) patients including 8 (8.5%) patients with serious AEs (uncontrolled bronchial hyperreactivity, N=5; serious hypoglycaemia, N=3). Some patients had one or more AEs, a total of 24 non-serious AEs was reported in 19 patients (sleep disturbances, N=9; respiratory disorders, N=5; digestive disorders, N=6). No cardiac adverse event was reported. Conclusion: This post-marketing surveillance drug study supports the good tolerance of Hemangiol® in children with IH. A rapid initiation protocol is of interest when treatment is urgent. The pre-therapeutic paediatric cardiology consultation should not be systematic but only indicated on specific patients. ClinicalTrials.gov: NCT 04105517.

Aims In the absence of a commonly agreed dosing protocol based on pharmacokinetic considerations, the dose and treatment duration for hydroxychloroquine (HCQ) COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. Methods We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. Results Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800mg day on D1 followed by 600mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. Conclusion Our results were clear indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best the benefit/risk balance.

The current drug safety landscape inadequately serves the millions of children prescribed medications every year. Randomized clinical trials are limited in detecting pediatric adverse drug effects due to low participant enrollment, complicated study design, and short trial duration. While the biology of human development and the pathology of childhood diseases are well studied research topics, current pharmacoepidemiology approaches do not use this knowledge when investigating drug safety in children. Here, we describe how adverse drug effects manifest as children develop from birth through the teenage years. We discuss the benefits of an empirical approach for evaluating clinical relevance and biological causality of identified adverse drug effects in children. We argue that a data-driven strategy that leverages observational data and biomedical knowledge is an ethical and effective methodology to improve pediatric drug safety.

Background: In Italy both the consumption of antibiotics and the prevalence of bacterial resistance are higher than in other European countries. In 2017, the first National Action Plan on Antimicrobial Resistance (PNCAR) was adopted in Italy. In response to the PNCAR two National Reports on Antibiotics’ use in the human setting have been published. The article’s aim is to describe the pattern of antibiotics consumption in the community setting in Italy from 2013 to 2018. Methods: In order to analyse the consumption for reimbursed antibiotics dispensed by community pharmacies different data sources were used. Consumption was measured in terms of Defined Daily Dose (DDD), prescriptions or prevalence of use. Results: In 2018, the consumption of antibiotics in Italy amounted to 16.1 DDD per 1,000 inhabitants per day. The rates of consumption by geographical area were: 12.7 DDD in the North, 16.9 in the Centre and 20.4 in the South. The use was greater in the extreme age groups than in the population aged from 20 to 64 years. The consumption was higher in winter season with high peaks in the incidence of flu syndromes. In the paediatric population, a utilization rate of 1,010 prescriptions per 1,000 children, with a prevalence of use of 40.8%, was found. Conclusion: The study provides useful information on geographical variability of antibiotics’ use in Italy to guide decision makers in the introduction of tailored interventions, as suggested by PNCAR, aimed at promoting a more rational use of antibiotics for humans and reducing antimicrobial resistance.

Aims: This study aimed to assess the impact of pharmacist-led medication therapy management (MTM) for ambulatory elderly patients with chronic diseases. Methods: Consecutive patients were enrolled from pharmacist outpatient clinics from January 2016 to June 2018. Eligible subjects were performed with MTM services by the pharmacists and had clinical data for at least 2 clinic visits within a consecutive 12-month period after the first MTM visit. The drug-related problems (DRPs) and recommendations were evaluated using The Pharmaceutical Care Network Europe (PCNE) Classification for Drug related problems V8.03. Results: A total of 525 DRPs were identified during the study period. Treatment effectiveness P1 (53.71%) was the most common problems of DRPs. The most frequently recommended intervention was changing the drug (48.76%). These interventions were accepted by the patients in 92.38% and were completely implemented in 90.48%. The number of drugs taken was the significant associated factor for DRPs. Post-intervention group showed lower levels in systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to the pre-intervention group. There were statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) between the pre- and post-intervention group. The average cost of medications per patient for every month decreased from 387.72 Ren Min Bi (RMB) to 355.17 RMB (P=0.009). Conclusion: We confirmed that pharmacists has a valuable role to perform MTM services for ambulatory elderly patients, not only in identifying and solving the DRPs, but also in improving clinical outcomes (BP and lipid level) and cost saving.

Purpose: The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. Methods: We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. Conclusions: The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3-weekly) or optimal average dose (cabazitaxel, nab-paclitaxel) has not been fully resolved, as it may differ per tumor entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has partly been explored for 3-weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab-paclitaxel at present.

Aims: To determine if the combination of exercise and statin could normalize postprandial triglyceridemia (PPTG) in hypercholesteraemic individuals. Mehods: Eight hypercholesteraemic (blood cholesterol 182±38 mg·dL-1; LDL-c 102±32 mg·dL-1) overweight (BMI 30±4 kg·m-2) individuals with metabolic syndrome (i.e., Met Synd) were compared to a group of eight metabolically healthy controls (i.e., MetH, blood cholesterol 149±23 mg·dL-1; LDL-c 77±23 mg·dL-1, and BMI 23±2 kg·m-2). Each group underwent two PPTG tests, either 14-h after a bout of intense exercise (EXER) or without previous exercise (REST). Additionally, Met Synd individuals were tested 96 h after withdrawal of their habitual statin medication (PLAC trials) to study medication effects. Results: A bout of exercise before the test meal did not reduce PPTG in Met Synd (P=0.347), but reduced PPTG by 46% in MetH (224±142 to 413±267 mg·dL-1·for 5 h iAUC; P=0.02). In both trials (i.e., REST and EXER) statin withdrawal in Met Synd greatly increased PPTG (average 65%; P<0.01), mean LDL-c (average 25%; P<0.01), total cholesterol (average 16%; P<0.01) and Apo B48 (24%; P<0.01), without interference from exercise. However, Apo B100 was not affected by statin withdrawal. Conclusions: Hypercholesteraemic Met Synd individuals (compared to metabolically healthy controls) are resistant to the effects of exercise on reducing PPTG. However, chronic statin medication blunts the elevations in TG after a fat meal (i.e., iAUC of PPTG) reducing their cardiovascular risk associated to their atherogenic dyslipidemia. Statin decreases PPTG by reducing the secretion or accelerating the catabolism of intestinal Apo B48.

Personalization of oral small molecule anticancer drug doses based on individual patient blood drug levels, also known as therapeutic drug monitoring or TDM, has the potential to significantly improve the effectiveness of treatment by maximizing drug efficacy and minimize toxicity. However, this option has not yet been widely embraced by the oncology community. Some reasons for this include increased logistical complexity of dose individualization, the lack of clinical laboratories that measure small molecule drug concentrations in support of patient care, and the lack of reimbursement of costs. However, the main obstacle may be the lack of studies clearly demonstrating that monitoring of oral small molecule anticancer drug levels actually improves clinical outcomes. Without unequivocal evidence in support of TDM-guided dose individualization, especially demonstration of improved survival with TDM in randomized controlled trials, wide acceptance of this approach by oncologists and reimbursement by insurance companies is unlikely, and patients may continue to suffer as a result of receiving incorrect drug doses. This article reviews the current status of therapeutic drug monitoring of oral small molecule drugs in oncology and intends to provide strategic insights into the design of studies for evaluating the utility of TDM in this clinical context.