Development of population biokinetic and dynamic model of radioactive iodine (131I) and application in dosage optimisation patients with benign thyroid disease

Cilj disertacije je bio da se primenom pristupa nelinearnog modelovanja kombinovanih efekata razvije populacioni model intratireoidne biokinetike 131I, kao i dinamički model verovatnoće ishoda terapije 131I kod pacijenata sa benignim oboljenjima štitaste žlezde. Podaci su prikupljeni retrospektivno iz medicinske dokumenatcije, a analiza je izvršena primenom programa NONMEM®. Kroz razvoj populacionog biokinetičkog modela 131I na osnovu rutinskih podataka o merenjima fiksacija 131I u štitastoj žlezdi nakon primene testne doza aktivnosti, ispitan je i kvantifikovan uticaj demografskih i kliničkih karakteristika pacijenata na biokinetiku 131I, kao i njena inter- i intraindividualna varijabilnost. Utvrđeno je da na brzinu preuzimanja 131I u štitastu žlezdu značajno utiču dijagnoza, starost, funkcionalni volumen štitaste žlezde, fT4, lečenje antitireoidnim lekovima, kao i vreme prekida terapije pre primene 131I, dok na brzinu eliminacije utiče starost pacijenta. Na osnovu podataka o ishodu terapije praćenog godinu dana nakon primene terapijske doze 131I razvijen je populacioni dinamički model proporcionalnih šansi. Pokazano je da od ispitivanih mera izloženosti biološki efektivna doza (BED) i apsorbovana doza zračenja statistički značajno bolje korelišu sa verovatnoćom ishodom u odnosu na dozu aktivnosti i maksimalnu brzinu apsorbovane doze, a BED je kao mera sa najnižom vrednošću Akaike informacionog kriterijuma uključena u finalni model. Na verovatnoću ishoda značajno utiče funkcionalni volumen štitaste žlezde. Rezultati ukazuju da bi primena BED formalizma mogla da doprinese personalizaciji terapije kroz individualizaciju vrednosti apsorbovane doze zračenja, kao i da bi ciljne vrednosti BED trebalo definisati za subpopulacije pacijenata sa različitim volumenom štitaste žlezde.The dissertation aimed to develop a population model of intra-thyroidal 131I biokinetics as well as a dynamic model of the 131I therapy outcome probability in patients with benign thyroid diseases using the nonlinear mixed-effects modelling approach. Data were collected retrospectively from medical records, and the analysis was performed using the NONMEM® software. Through the development of the population biokinetic model 131I, based on routine data on 131I thyroidal uptake measurements after application of a tracer activity dose, the influence of patients' demographic and clinical characteristics on 131I biokinetics, as well as inter-, and intraindividual variability was examined and quantified. The rate of 131I uptake was significantly affected by diagnosis, functional thyroid volume, age, fT4, application of antithyroid drugs, and the therapy discontinuation time before 131I administration, while the rate of elimination was affected by the patient's age. The population dynamic proportional odds model was developed based on the data of therapy outcomes monitored one year after the application of the 131I therapeutic dose. It was found that, among the investigated exposure measures, the biologically effective dose (BED) and absorbed radiation dose correlated significantly better with the probability of an outcome than the activity dose and the maximum absorbed dose rate. As the measure with the lowest value of the Akaike information criterion, BED was included in the final model. The probability of the therapy outcome is significantly affected by the functional thyroid volume. The results indicate that the application of BED formalism could contribute to the personalization of therapy through individualization of the absorbed dose values and that the target values of BED should be defined for subpopulations of patients with different thyroid volumes

Klinički značajne interakcije opioidnih i neopioidnih analgetika

Patients often seek advise from doctors and pharmacists about pain treatment. Opioid and non-opioid analgesics are the most commonly used drugs in the treatment of pain, but they have potential for pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of central nervous system depression and respiratory depression is increased if opioid analgesics are used with anxiolytics, first-generation antihistamines, and antidepressants. Serotonin syndrome can occur if tramadol and fentanyl are used with selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline inhibitors, monoamino oxidase inhibitors, etc. Decreased elimination of opioid analgesics as a consequence of CYP2D6 and CYP3A4 isoenzyme inhibition can result in their increased efficacy but sedation and respiratory depression have also been reported. Caution is needed when non-steroidal anti-inflammatory drugs (NSAIDs) are used concomitantly with other drugs that cause bleeding such as anticoagulants and SSRIs or drugs that decrease the elimination of NSAIDs by inhibition of CYP2C9. NSAIDs can antagonize the effect of antihypertensives, and interaction with angiotensin-converting enzyme inhibitors may result in renal failure. In comparison with opioid analgesics and NSAIDs, paracetamol has the lowest potential for clinically significant interactions. The prophylactic administration of paracetamol after vaccination should be avoided and patients should be advised not to use alcohol during therapy.Pacijenti se često obraćaju lekarima i farmaceutima za pomoć u terapiji bola. Opioidni i neopioidni analgetici su najčešće lekovi izbora u terapiji bola ali imaju veliki potencijal za stupanje u farmakodinamske i farmakokinetičke interakcije sa drugim lekovima. Kod opioidnih analgetika povećan je rizik od pojave depresije centralnog nervnog sistema i respiratorne depresije ukoliko se ovi lekovi primenjuju sa anksioliticima, antihistaminicima prve generacije i antidepresivima. Serotoninski sindrom se može javiti ukoliko se tramadol i fentanil primenjuju sa selektivnim inhibitorima preuzimanja serotonina (SSRI), inhibitorima preuzimanja serotonina i noradrenalina, inhibitorima monoamino-oksidaze i dr. Usporena eliminacija opioidnih analgetika, kao posledica inhibicije izoenzima CYP2D6 i CYP3A4 može rezultirati njihovom povećanom efikasnošću ali i pojavom sedacije i respiratorne depresije. Oprez je potreban kada se nesteroidni antiinflamatorni lekovi (NSAIL) primenjuju istovremeno sa drugim lekovima koji mogu dovesti do krvarenja poput antikoagulanasa i SSRI ili lekovima koji usporavaju eliminaciju NSAIL inhibicijom izoenzima CYP2C9. NSAIL mogu antagonizovati dejstvo antihipertenziva, a interakcija sa inhibitorima angiotenzin-konvertujućeg enzima može rezultirati bubrežnom insuficijencijom. U poređenju sa opioidnim analgeticima i NSAIL, paracetamol ima najmanji potencijal za stupanje u klinički značajne interakcije. Potrebno je izbegavati profilaktičku primenu paracetamola nakon vakcinacije i skrenuti pacijentima pažnju da ne primenjuju alkohol u toku terapije

Izazovi i stavovi o doziranju radioaktivnog joda u terapiji benignih oboljenja štitaste žlijezde

Radioactive iodine represents the significant therapeutic option in the treatment of benign thyroid disease. Despite a decades-long experience and a large number of treated patients, many issues related to the therapy with radioactive iodine are still under discussion, including the method of therapeutic dose determination and the factors that affect the therapy outcome. Clinical practice, as well as recommendations of the relevant guidelines in terms of the dosing of radioactive iodine, vary widely in the world: from the fixed dose application to the complex dosimetric protocols. A greater presence of dosimetric approach would facilitate the establishment of dose-effect correlation and the study of influence of various factors on the therapy outcome. Development of the new dosing protocols, as well as new insights into factors that affect therapeutic outcome, enable further improvement of both efficacy and safety of the radioactive iodine therapy for an individual patient.Radioaktivni jod predstavlja značajnu terapijsku opciju u liječenju benignih oboljenja štitaste žlijezde. Uprkos višedecenijskom iskustvu i velikom broju liječenih pacijenata, mnoga pitanja vezana za terapiju radioaktivnim jodom još su uvijek predmet diskusija, uključujući način određivanja terapijske doze, kao i faktore koji utiču na ishod terapije. Klinička praksa, kao i preporuke odgovarajućih vodiča u pogledu doziranja radioaktivnog joda široko variraju u svijetu, od primjene fiksnih doza do kompleksnih dozimetrijskih protokola. Veća zastupljenost dozimetrijskog pristupa olakšala bi uspostavljanje korelacije doza-efekat i proučavanje uticaja raznih faktora na ishod terapije. Razvoj novih protokola za izračunavanje terapijske doze aktivnosti, kao i nova saznanja o faktorima koji utiču na ishod terapije omogućavaju dalje unaprijeđenje kako efikasnosti, tako i bezbjednosti terapije radioaktivnim jodom za individualnog pacijenta

Koncept i upotreba populacionih farmakokinetičkih i farmakokinetičko/farmakodinamičkih modela u razvoju leka i kliničkoj praksi

Due to frequent clinical trial failures and consequently fewer new drug approvals, the need for improvement in drug development has, to a certain extent, been met using model-based drug development. Pharmacometrics is a part of pharmacology that quantifies drug behaviour, treatment response and disease progression based on different models (pharmacokinetic - PK, pharmacodynamic - PD, PK/PD models, etc.) and simulations. Regulatory bodies (European Medicines Agency, Food and Drug Administration) encourage the use of modelling and simulations to facilitate decision-making throughout all drug development phases. Moreover, the identification of factors that contribute to variability provides a basis for dose individualisation in routine clinical practice. This review summarises current knowledge regarding the application of pharmacometrics in drug development and clinical practice with emphasis on the population modelling approach.Usled čestih neuspeha u kliničkim ispitivanjima i posledično manjeg broja odobrenja novih lekova, potreba za poboljšanjem u razvoju lekova je u određenoj meri zadovoljena korišćenjem pristupa razvoja lekova zasnovanog na modelu. Farmakometrija predstavlja granu farmakologije koja kvantifikuje ponašanje leka, odgovor na terapiju i napredovanje bolesti na osnovu različitih modela (farmakokinetički - FK, farmakodinamički - FD, FK/FD modeli itd.) i simulacija. Regulatorna tela (Evropska agencija za lekove, Uprava za hranu i lekove) podstiču primenu modelovanja i simulacija u svrhu lakšeg donošenja odluka tokom svih faza razvoja lekova. Štaviše, identifikacija faktora koji doprinose varijabilnosti predstavlja osnovu za individualizaciju doze u rutinskoj kliničkoj praksi. Ovaj revijalni rad sumira trenutno znanje u vezi sa primenom farmakometrije u razvoju lekova i kliničkoj praksi sa fokusom na populacionu analizu

Integrating Clopidogrel’s First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85–90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants’ data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study’s generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA

Clinically important drug interactions with opioid and non-opioid analgesics

Patients often seek advise from doctors and pharmacists about pain treatment. Opioid and non-opioid analgesics are the most commonly used drugs in the treatment of pain, but they have potential for pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of central nervous system depression and respiratory depression is increased if opioid analgesics are used with anxiolytics, first-generation antihistamines, and antidepressants. Serotonin syndrome can occur if tramadol and fentanyl are used with selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline inhibitors, monoamino oxidase inhibitors, etc. Decreased elimination of opioid analgesics as a consequence of CYP2D6 and CYP3A4 isoenzyme inhibition can result in their increased efficacy but sedation and respiratory depression have also been reported. Caution is needed when non-steroidal anti-inflammatory drugs (NSAIDs) are used concomitantly with other drugs that cause bleeding such as anticoagulants and SSRIs or drugs that decrease the elimination of NSAIDs by inhibition of CYP2C9. NSAIDs can antagonize the effect of antihypertensives, and interaction with angiotensin-converting enzyme inhibitors may result in renal failure. In comparison with opioid analgesics and NSAIDs, paracetamol has the lowest potential for clinically significant interactions. The prophylactic administration of paracetamol after vaccination should be avoided and patients should be advised not to use alcohol during therapy

Clinically important drug interactions with opioid and non-opioid analgesics

Patients often seek advise from doctors and pharmacists about pain treatment. Opioid and non-opioid analgesics are the most commonly used drugs in the treatment of pain, but they have potential for pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of central nervous system depression and respiratory depression is increased if opioid analgesics are used with anxiolytics, first-generation antihistamines, and antidepressants. Serotonin syndrome can occur if tramadol and fentanyl are used with selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline inhibitors, monoamino oxidase inhibitors, etc. Decreased elimination of opioid analgesics as a consequence of CYP2D6 and CYP3A4 isoenzyme inhibition can result in their increased efficacy but sedation and respiratory depression have also been reported. Caution is needed when non-steroidal anti-inflammatory drugs (NSAIDs) are used concomitantly with other drugs that cause bleeding such as anticoagulants and SSRIs or drugs that decrease the elimination of NSAIDs by inhibition of CYP2C9. NSAIDs can antagonize the effect of antihypertensives, and interaction with angiotensin-converting enzyme inhibitors may result in renal failure. In comparison with opioid analgesics and NSAIDs, paracetamol has the lowest potential for clinically significant interactions. The prophylactic administration of paracetamol after vaccination should be avoided and patients should be advised not to use alcohol during therapy

Population exposure-response model of 131I in patients with benign thyroid disease

Purpose: The study aimed to explore the relationship of different exposure measures with 131I therapy response in patients with benign thyroid disease, estimate the variability in the response, investigate possible covariates, and discuss dosing implications of the results. Methods: A population exposure-response analysis was performed using nonlinear mixed-effects modelling. Data from 95 adult patients with benign thyroid disease were analysed. Evaluated exposure parameters were: administered radioactivity dose (Aa) [MBq], total absorbed dose (ABD) [Gy], maximum of absorbed dose-rate (MXR) [Gy/h] and biologically effective dose (BED) [Gy]. The response was modelled as ordered categorical data: hyper-, eu- and hypothyroidism. The final model performance was evaluated by a visual predictive check. Results: The probability of the outcome following 131I therapy was best described by a proportional-odds model, including the log-linear model of 131I effect and the exponential model of the response-time relationship. All exposure measures were statistically significant with p<0.001, with BED and ABD being statistically better than the other two. Nevertheless, as BED resulted in the lowest AIC value, it was included in the final model. Accordingly, BED value of 289.7 Gy is associated with 80% probability of successful treatment outcome 12 months after 131I application in patients with median thyroid volume (32.28 mL). The target thyroid volume was a statistically significant covariate. The visual predictive check of the final model showed good model performance. Conclusion: Our results imply that BED formalism could aid in therapy individualisation. The larger thyroid volume is associated with a lower probability of a successful outcome

The influence of biologically effective dose (BED) on the 131I therapy response in patients with benign thyroid disease – nonlinear mixed effect modelling approach

Aim. The purpose of the study was to explore the influence of biologically effective dose (BED [Gy]), the administered radioactivity dose (Aa [MBq]), the total absorbed dose (ABD [Gy]), the maximum of absorbed dose-rate (MXR [Gy/h]) to radioactive iodine (131I) on the response in patients with benign thyroid disease. Materials and methods. Data from adult patients with benign thyroid disease who had previously received a test dose of 131I activity were included in the analysis. Individual thyroid exposure parameters were estimated from the population biokinetic 131I model and the therapeutic activity doses (in range from 185 to 1300 MBq). Patients response was followed up at periodic intervals, starting from 4-6 weeks, up to one year after the administration of 131I. A successful clinical outcome was resolution of of hyperthyroidism. A population exposure-response analysis was performed using nonlinear mixed-effects modelling using NONMEM® (v. 7.4). The response data was modelled as ordered categorical with three levels (hyper-, eu- and hypothyroidism). The performance of the final model was evaluated using visual predictive check (VPC). Results. In total 95 adult patients were analyzed, including 57 (60%) with Graves’ disease, 22 (23.2%) with toxic multinodular goiter and 16 (16.8%) with toxic adenoma. The probability of the outcome was best described by a proportional-odds model, including the log-linear model of 131I effect and the exponential model of the response-time relationship. Among all tested exposure measures, BED was included in the final model. Its inclusion in the base model was statistically significant (p<0.001). The value of 289.7 Gy was associated with 80% probability of successful treatment outcome one year after 131I application in patients with median thyroid volume of 32.28 mL. Conclusion. The results indicate that using BED formalism could lead to a better individualisation of the therapy. The larger thyroid volume is associated with a lower probability of a successful outcome. References. Topic Vucenovic V, Rajkovaca Z, Jelic D, Stanimirovic D, Vuleta G, Miljkovic B, Vucicevic K. Investigation of factors influencing radioiodine ((131)I) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach. Eur J Clin Pharmacol. 2018;74(8):1037-1045. European Commission. Council Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation, and repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (2014). Official Journal of the European Union L13/2014 57:1-73. doi:10.3000/19770677.L_2014.013.eng Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016;26(10):1343-1421.PAGANZ, Sydney 2021 Virtual Meeting: 27th-29th Januar

Investigation of factors influencing radioiodine (I-131) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach

Radioiodine (I-131) therapy is the common treatment option for benign thyroid diseases. The objective of this study was to characterize I-131 biokinetics in patients with benign thyroid disease and to investigate and quantify the influence of patients' demographic and clinical characteristics on intra-thyroidal I-131 kinetics by developing a population model. Population pharmacokinetic analysis was performed using a nonlinear mixed effects approach. Data sets of 345 adult patients with benign thyroid disease, retrospectively collected from patients' medical records, were evaluated in the analysis. The two-compartment model of I-131 biokinetics representing the blood compartment and thyroid gland was used as the structural model. Results of the study indicate that the rate constant of the uptake of I-131 into the thyroid (k (tu)) is significantly influenced by clinical diagnosis, age, functional thyroid volume, free thyroxine in plasma (fT(4)), use of anti-thyroid drugs, and time of discontinuation of therapy before administration of the radioiodine (THDT), while the effective half-life of I-131 is affected by the age of the patients. Inclusion of the covariates in the base model resulted in a decrease of the between subject variability for k (tu) from 91 (3.9) to 53.9 (4.5)%. This is the first population model that accounts for the influence of fT(4) and THDT on radioiodine kinetics. The model could be used for further investigations into the correlation between thyroidal exposure to I-131 and the outcome of radioiodine therapy of benign thyroid disease as well as the development of dosing recommendations