Browsing by Subject "pharmacokinetics"

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  • Goncalves, Bronner P.; Pett, Helmi; Tiono, Alfred B.; Murry, Daryl; Sirima, Sodiomon B.; Niemi, Mikko; Bousema, Teun; Drakeley, Chris; ter Heine, Rob (2017)
    Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine.
  • Jaatinen, Hannakaisa (Helsingfors universitet, 2016)
    This thesis work was carried out in Biology Section of Experimental Therapeutics Programme in Spanish National Cancer Research Center in Madrid. The aim of this work was to carry out characterization of ADME profile of novel protein kinase inhibitors synthesized by the Medicinal Chemistry Section of Experimental Therapeutics Programme. ADME refers to absorption, distribution, metabolism and excretion. ADME screening provides crucial information when choosing new chemical entities (NCEs) and lead compounds with desirable properties for further development and for clinical studies. ADME screening is carried out in the early discovery phase in order to avoid costly failures in the later stages. The protein kinase inhibitors used in this work were designed against three different targets. However, the targets cannot be disclosed in this work due to confidentiality reasons and thus they will be referred to as X, Y, and Z. The ADME characterization was performed in a high-throughput format to screen fast compounds with desired properties. To carry out ADME characterization for the novel compounds, several in vitro assays and in vivo pharmacokinetic studies were carried out. The work was started by setting up an LC-MS/MS detection method for each compound. All in all, LC-MS/MS detection method was set up for 63 new compounds. The detection method was used to analyze the results of different in vitro and in vivo studies. In vitro assays included kinetic solubility assay, parallel artificial membrane permeability assay (PAMPA), microsomal metabolic stability assay, plasma protein binding assay, and solubility in biological fluids. The solubility in biological fluids assay was performed only for the two compounds that were selected for the pharmacokinetic (PK) study. Pharmacokinetic properties of the compounds selected for the pharmacokinetic study using the Balb/C mice were further analyzed by their pharmacokinetic parameters. These parameters were calculated by applying non-compartmental model in the WinNonlin software. One compound, ETP-871, showed promising results in the pharmacokinetic study. Another compound ETP-827 was cleared too fast from the body. Too fast excretion is undesirable since low plasma concentration of the drug is insufficient to reach the therapeutic effect. For the compound ETP-827 a new PK study with higher dose was carried out. Due to the confidentiality reasons, these further studies are not presented in this work.
  • Fontana, Vanessa; Turner, Richard Myles; Francis, Ben; Yin, Peng; Pütz, Benno; Hiltunen, Timo P.; Ruotsalainen, Sanni; Kontula, Kimmo K.; Müller-Myhsok, Bertam; Pirmohamed, Munir (2022)
    Purpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes. Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects. Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17 x10(-9)) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54 x10(-8)). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3 x10(-5)), but not with rs116702638. Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.
  • Bäckström, Mia (Helsingfors universitet, 2017)
    Background: Dexmedetomdine is a α2-adrenergic receptor agonist, which by binding to the α2-adrenergic receptor in the sympathetic nervous system exhibits sedative effect. Additionally, it has an analgesic and anxiolytic effect. Dexmedetomidine is registered as a sedative for use in the intensive care unit and in USA, additionally, in surgical settings. The study was conducted to characterize the pharmacokinetics in healthy volunteers through pharmacokinetic analysis methods. Methods: The clinical study was conducted on healthy 10 voluntary subjects each receiving dose of 1 µg/kg both intravenously (IV) and subcutaneously (SC). The study session lasted for 10 hours, with a wash-out period of at least 7 days between consecutive administrations. Arterial blood samples were taken to determine the plasma concentrations of dexmedetomidine. The pharmacokinetics of the IV and SC dose were determined by noncompartmental analysis (NCA) and, additionally, population modeling using nonlinear mixed effects model (NONMEM) was used to determine the pharmacokinetics of the IV dose. Results: The population's mean clearance after the IV dose was 40.0 L/h and for SC 45.6 L/h. The elimination half-life was 2 hours for IV, whereas terminal half-life was 9 hours for the SC dose. The SC bioavailability was 120 %. From the population modeling the typical elimination clearance, volume of distribution in central compartment, inter-compartmental clearance, and volume of distribution in the second compartment were 39.6 L/h, 13.7 L, 116 L/h, and 77 L, respectively. Conclussion: The obtained pharmacokinetic parameter values from NCA for IV were in line with the results from previous studies. For the SC dose the pharmacokinetic parameter values had high SD indicating high inter-individual variations. However, when the 8th subject was excluded from data analysis less SD was obtained and the result resembled more the results from other extravascular studies. The pharmacokinetic population results for IV dexmedetomidine were similar to previous studies on healthy subjects. Weight was used as a covariate, and was modeled by allometrically scaling the parameters. From the results it is shown that the covariate improved the model's goodness of fit.
  • Heilkkinen, Emma M.; Auriola, Seppo; Ranta, Veli-Pekka; Demarais, Nicholas J.; Grey, Angus C.; del Amo, Eva M.; Toropainen, Elisa; Vellonen, Kati-Sisko; Urtti, Arto; Ruponen, Marika (2019)
    Lens is the avascular tissue in the eye between the aqueous humor and vitreous. Drug binding to the lens might affect ocular pharmacokinetics, and the binding may also have a pharmacological role in drug-induced cataract and cataract treatment. Drug distribution in the lens has been studied in vitro with many compounds; however, the experimental methods vary, no detailed information on distribution between the lens sublayers exist, and the partition coefficients are reported rarely. Therefore, our objectives were to clarify drug localization in the lens layers and establish partition coefficients for a wide range of molecules. Furthermore, we aimed to illustrate the effect of lenticular drug binding on overall ocular drug pharmacokinetics. We studied the distribution of 16 drugs and three fluorescent dyes in whole porcine lenses in vitro with imaging mass spectrometry and fluorescence microscopy techniques. Furthermore, we determined lens/buffer partition coefficients with the same experimental setup for 28 drugs with mass spectrometry. Finally, the effect of lenticular binding of drugs on aqueous humor drug exposure was explored with pharmacokinetic simulations. After 4 h, the drugs and the dyes distributed only to the outermost lens layers (capsule and cortex). The lens/buffer partition coefficients for the drugs were low, ranging from 0.05 to 0.8. On the basis of the pharmacokinetic simulations, a high lens-aqueous humor partition coefficient increases drug exposure in the lens but does not significantly alter the pharmacokinetics in the aqueous humor. To conclude, the lens seems to act mainly as a physical barrier for drug distribution in the eye, and drug binding to the lens affects mainly the drug pharmacokinetics in the lens.
  • Hirvensalo, Päivi; Tornio, Aleksi; Neuvonen, Mikko; Kiander, Wilma; Kidron, Heidi; Paile-Hyvärinen, Maria; Tapaninen, Tuija; Backman, Janne T.; Niemi, Mikko (2019)
    Abstract The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S- and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 ? 10-9 and P = 3.19 ? 10-12). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 ? 10-8). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single nucleotide variations (SNVs) may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity. This article is protected by copyright. All rights reserved.
  • Vermeulen, Eric; van den Anker, John N.; Della Pasqua, Oscar; Hoppu, Kaarlo; van der Lee, Johanna H.; GRiP (2017)
    Objectives In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. Methods Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies. Key findings The importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose-ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose-finding study. Conclusions The emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing.
  • Iso-Mustajärvi, Ilona (Helsingfors universitet, 2013)
  • Olkkola, Aleksi (Helsingin yliopisto, 2019)
    Tutkimuksen tausta: Ibrutinibi on Brutonin tyrosiinikinaasin inhibiittori, jota käytetään kroonisen lymfaattisen leukemian (KLL), Waldenströmin makroglobulinemian, erilaisten lymfoomien ja kroonisen käänteishyljintäsairauden hoidossa. Se on tehokas etenkin KLL:n hoidossa, mutta sen käyttöä rajoittaa lääkityksen korkea hinta. Ibrutinibilla on pieni oraalinen biologinen hyötyosuus lähinnä merkittävän ensikierron metabolian vuoksi. Veritautia sairastavat potilaat ovat alttiita saamaan syviä sieni-infektioita niin itse taudin kuin sen hoitojenkin vuoksi. Sieni-infektioiden ehkäisy ja hoito ibrutinibia käyttävillä potilailla on kuitenkin ongelmallista, koska ibrutinibi on herkkä CYP3A4- välitteisille lääkeyhteisvaikutuksille ja suun kautta otettavat sienilääkkeet estävät kyseistä entsyymiä. Tutkimuksen tarkoitus oli selvittää sieni-infektioiden hoidossa käytetyn itrakonatsolin vaikutus ibrutinibin farmakokinetiikkaan ja voisiko lääkkeiden interaktiota käyttää hyväksi. Menetelmät: Kyseessä oli randomoitu, kaksivaiheinen, plasebokontrolloitu crossover-tutkimus. Tutkimukseen valittiin 11 tervettä ja tupakoimatonta vapaaehtoista miestä. Tutkittaville annettiin joko plaseboa tai 200 mg itrakonatsolia ensimmäisenä päivänä klo 8 ja 20 ja päivinä 2-4 klo 8. Kolmantena päivänä tutkittavat saivat joko 140 mg ibrutinibia plasebovaiheessa tai 15 mg ibrutinibia itrakonatsolivaiheessa noin tunti aamupalan jälkeen klo 9. Tutkittavista otettiin laskimoverinäytteitä säännöllisin väliajoin. Tulokset: Itrakonatsoli kymmenkertaisti altistumisen ibrutinibille verrattuna plaseboon. Lisäksi itrakonatsoli vähensi merkittävästi ibrutinibin pitoisuuksien vaihtelua yksilöiden välillä. Johtopäätökset: Ibrutinibin ja itrakonatsolin yhteiskäyttö voisi olla keino vähentää merkittävästi ibrutinibihoidon kustannuksia ja vaihtelua ibrutinibin pitoisuuksissa yksilöiden välillä. Lisäksi itrakonatsoli voisi tarjota samalla suojaa syviä sieni-infektioita vastaan.
  • Keltto, Katri (Helsingfors universitet, 2011)
    Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used for the treatment of pain in sheep and swine. Information of correct ketoprofen doses in different animal species is limited. The correct dose cannot be reliably extrapolated based on other species or human. The problem in cases of suspected overdose is knowing whether the given dose was toxic. The objective of the study with sheep was to figure out if the kinetics of ketoprofen is altered by a tenfold overdose, study the effect of the overdose to kidneys and find out a way to diagnose overdose by a simple urine test. The objective of the study with swine was to figure out the bioavailability and pharmacokinetics of ketoprofen after oral, intramuscular and intravenous administration. The most important variables were AUC0-_, Cmax and Tmax. Bioavailability was calculated based on intravascular administration. 30 mg/kg ketoprofen was administered intravenously to six sheep. The concentration of ketoprofen in sheep plasma was followed for 24 hours. Pharmacokinetic parameters were calculated afterwards. Blood and urine samples were analysed to detect enzyme markers indicating possible renal failure. The sheep were finished off 24 hours after the administration and the possible damage to kidneys was evaluated from histological samples. Ketoprofen was also administered to eight swine. The doses were 3 mg/kg of oral, intramuscular and intravascular, and 6 mg/kg of oral ketoprofen. The study was performed as a randomized, cross-over study. The concentration of ketoprofen in swine plasma was followed for 48 hours after administration. Pharmacokinetic parameters were calculated and bioequivalence evaluated afterwards. The in vivo -studies of both of the studies as well as the histological study of the kidneys, and the urine and blood analysis except for the analysis of ketoprofen concentration, were carried out by the researchers of the Faculty of Veterinary Medicine. Plasma ketoprofen concentrations were measured by high-performance liquid chromatography (HPLC). Drug concentration and pharmacokinetic analysis were carried out in the Faculty of Pharmacy. The tenfold dose of ketoprofen was toxic in sheep. Serum concentrations of urea and creatinine increased. Histological samples revealed acute tubular damage. Many urine enzyme concentrations increased. The rise of urine lactate dehydrogenase (LD) concentration was most significant and earliest. LD appears to be a potential marker of a toxic ketoprofen dose. Compared with the therapeutic dose, overdose did not affect ketoprofen elimination rate from plasma, so the kinetics of ketoprofen was not altered. AUC- and Cmax -values were over tenfold compared to the therapeutic dose, so the values did not rise linearly as the dose reached a toxic level. Bioequivalence of ketoprofen in swine was not observed between different routes of administration. The bioavailability was excellent in all routes of administration. Tmax was slightly over one hour after administration. Cmax and AUC were 5,1 mg/l and 32 mg l-1 h after oral 3 mg/kg dose and 7,6 mg/l and 37 mg l-1 h after intramuscular dose. The increases in AUC and Cmax were linear between the different dosages of oral ketoprofen. The difference of the elimination rates between oral and intravascular administration was statistically significant. Ketoprofen distribution volume and clearance did not differ significantly between different routes of administration.
  • Valitalo, Pyry; Kokki, Merja; Ranta, Veli-Pekka; Olkkola, Klaus T.; Hooker, Andrew C.; Kokki, Hannu (2017)
    Purpose The aim of the current population pharmacokinetic study was to quantify oxycodone pharmacokinetics in children ranging from preterm neonates to children up to 7 years of age. Methods Data on intravenous or intramuscular oxycodone administration were obtained from three previously published studies (n = 119). The median [range] postmenstrual age of the subjects was 299 days [170 days-7.8 years]. A population pharmacokinetic model was built using 781 measurements of oxycodone plasma concentration. The model was used to simulate repeated intravenous oxycodone administration in four representative infants covering the age range from an extremely preterm neonate to 1-year old infant. Results The rapid maturation of oxycodone clearance was best described with combined allometric scaling and maturation function. Central and peripheral volumes of distribution were nonlinearly related to bodyweight. The simulations on repeated intravenous administration in virtual patients indicated that oxycodone plasma concentration can be kept between 10 and 50 ng/ml with a high probability when the maintenance dose is calculated using the typical clearance and the dose interval is 4 h. Conclustions Oxycodone clearance matures rapidly after birth, and between-subject variability is pronounced in neonates. The pharmacokinetic model developed may be used to evaluate different multiple dosing regimens, but the safety of repeated doses should be ensured.
  • Correia, Cristiana; Ferreira, Abigail; Santos, Joana; Lapa, Rui; Yliperttula, Marjo; Urtti, Arto; Vale, Nuno (2021)
    Pharmacokinetic (PK) studies improve the design of dosing regimens in preclinical and clinical settings. In complex diseases like cancer, single-agent approaches are often insufficient for an effective treatment, and drug combination therapies can be implemented. In this work, in silico PK models were developed based on in vitro assays results, with the goal of predicting the in vivo performance of drug combinations in the context of cancer therapy. Combinations of reference drugs for cancer treatment, gemcitabine and 5-fluorouracil (5-FU), and repurposed drugs itraconazole, verapamil or tacrine, were evaluated in vitro. Then, two-compartment PK models were developed based on the previous in vitro studies and on the PK profile reported in the literature for human patients. Considering the quantification parameter area under the dose-response-time curve (AUC(effect)) for the combinations effect, itraconazole was the most effective in combination with either reference anticancer drugs. In addition, cell growth inhibition was itraconazole-dose dependent and an increase in effect was predicted if itraconazole administration was continued (24-h dosing interval). This work demonstrates that in silico methods and AUC(effect) are powerful tools to study relationships between tissue drug concentration and the percentage of cell growth inhibition over time.
  • Hakomäki, Henriikka; Kokki, Hannu; Lehtonen, Marko; Ranta, Veli-Pekka; Räsänen, Juha; Voipio, Hanna-Marja; Kokki, Merja (2021)
    Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 mu g/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 mu g/L and 0.04 mu g/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum-maximum), were C-max 4.31 mu g/L (1.93-15.5), AUC(inf) 2.89 h*mu g/L (1.72-40.2), CL 3.39 L/h/kg (0.25-6.02), terminal t1/2 1.75 h (1.07-31.0), V-ss 8.04 L/kg (1.05-49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half-lives for six subjects, and a wide between-subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans.
  • Kickova, Eva; Sadeghi, Amir; Puranen, Jooseppi; Tavakoli, Shirin; Sen, Merve; Ranta, Veli-Pekka; Arango-Gonzalez, Blanca; Bolz, Sylvia; Ueffing, Marius; Salmaso, Stefano; Caliceti, Paolo; Toropainen, Elisa; Ruponen, Marika; Urtti, Arto (2022)
    The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (approximate to 67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan-dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 +/- 29 nm). Intravitreal injections of pullulan and pullulan-dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Muller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan-dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan-dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.
  • Mian, P.; van Esdonk, M. J.; Olkkola, K. T.; de Winter, B. C. M.; Liukas, A.; Spriet, I.; Tibboel, D.; Petrovic, M.; Koch, B. C. P.; Allegaert, K. (2019)
    Aims Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean) of 10 mg l(-1) as target for effective analgesia. Methods A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. Results A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a C-ss of 9.2 mg l(-1) and 7.2 mg l(-1), for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in C-ss above 5.4 and 4.1 mg l(-1), respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. Conclusions The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.
  • Loescher, Wolfgang; Kaila, Kai (2021)
    In this response to a commentary by Ben-Ari and Delpire on our recent study on the pharmacology of neonatal seizures in a novel, physiologically validated rat model of birth asphyxia, we wish to rectify their inaccurate descriptions of our model and data. Furthermore, because Ben-Ari and Delpire suggest that negative data on bumetanide from preclinical and clinical trials of neonatal seizures have few implications for (alleged) bumetanide actions on neurons in other brain disorders, we will discuss this topic as well. Based on the poor brain penetration of bumetanide, combined with the extremely wide cellular expression patterns of the target protein NKCC1, it is obvious that the numerous actions of systemically applied bumetanide described in the literature are not mediated by the drug's effects on central neurons.
  • Pozharitskaya, Olga N.; Shikov, Alexander N.; Obluchinskaya, Ekaterina D.; Vuorela, Heikki (2019)
    Fucoidan, a fucose-rich polysaccharide from brown algae, has been used for transdermal formulations targeting inflammatory skin conditions, for the treatment of thrombosis, vascular permeability diseases, subcutaneous wounds, and burns. However, the pharmacokinetics of fucoidan after topical application has not been described. In this study, an ointment (OF) containing 15% fucoidan was topically applied to rats at the doses of 50-150 mg/g. The anti-Xa activity was selected as the biomarker, and the amidolytic assay method was validated and applied for pharmacokinetic studies of fucoidan. Fucoidan in OF penetrated the skin and distributed into the skin, striated muscle, and plasma with AUC(0-48) = 0.94 mu gh/g, 2.22 mu gh/g, and 1.92 mu gh/mL, respectively. The longest half-life for fucoidan was observed in plasma, then in striated muscle and skin. It was found that the pharmacokinetics of fucoidan after topical OF application was linear, in the range of 50-150 mg/kg. No accumulation of fucoidan in plasma was observed after repeated topical applications of 100 mg/kg during five days. Our results support the rationality of topical application of formulations with fucoidan.
  • Tornio, Aleksi; Filppula, Anne M.; Backman, Janne T. (2022)
    Multimorbidity, polypharmacotherapy and drug interactions are increasingly common in the ageing population. Many drug-drug interactions (DDIs) are caused by perpetrator drugs inhibiting or inducing cytochrome P450 (CYP) enzymes, resulting in alterations of the plasma concentrations of a victim drug. DDIs can have a major negative health impact, and in the past, unrecognized DDIs have resulted in drug withdrawals from the market. Signals to investigate DDIs may emerge from a variety of sources. Nowadays, standard methods are widely available to identify and characterize the mechanisms of CYP-mediated DDIs in vitro. Clinical pharmacokinetic studies, in turn, provide experimental data on pharmacokinetic outcomes of DDIs. Physiologically based pharmacokinetic (PBPK) modelling utilizing both in vitro and in vivo data is a powerful tool to predict different DDI scenarios. Finally, epidemiological studies can provide estimates on the health outcomes of DDIs. Thus, to fully characterize the mechanisms, clinical effects and implications of CYP-mediated DDIs, translational research approaches are required. This minireview provides an overview of translational approaches to study CYP-mediated DDIs, going beyond regulatory DDI guidelines, and an illustrative case study of how the DDI potential of clopidogrel was unveiled by combining these different methods.