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  • Tornio, Aleksi; Filppula, Anne M.; Niemi, Mikko; Backman, Janne T. (2019)
    Many drug-drug interactions (DDIs) are based on alterations of the plasma concentrations of a victim drug due to another drug causing inhibition and/or induction of the metabolism or transporter-mediated disposition of the victim drug. In the worst case, such interactions cause more than tenfold increases or decreases in victim drug exposure, with potentially life-threatening consequences. There has been tremendous progress in the predictability and modeling of DDIs. Accordingly, the combination of modeling approaches and clinical studies is the current mainstay in evaluation of the pharmacokinetic DDI risks of drugs. In this paper, we focus on the methodology of clinical studies on DDIs involving drug metabolism or transport. We specifically present considerations related to general DDI study designs, recommended enzyme and transporter index substrates and inhibitors, pharmacogenetic perspectives, index drug cocktails, endogenous substrates, limited sampling strategies, physiologically-based pharmacokinetic modeling, complex DDIs, methodological pitfalls, and interpretation of DDI information.
  • Itkonen, Matti K.; Tornio, Aleksi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2019)
    A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabo-lites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC(0-infinity)) and peak plasma concentration (C-max) of desloratadine to 280% (P = 3 x 10(-7)) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 x 10(-7)) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC(0-71h) to 52% (P = 5 x 10(-5)) and 6%(P = 2 X 10(-8)), respectively. Moreover, the 3-hydroxydesloratadine: desloratadine AUC(0-71h) ratios were 21% (P = 7 x 10(-10)) and 1.7% (P = 8 x 10(-11)) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.
  • Itkonen, Matti K.; Tornio, Aleksi; Filppula, Anne M.; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2018)
    The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.
  • Itkonen, Matti K.; Tornio, Aleksi; Lapatto-Reiniluoto, Outi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2019)
    Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC(0-infinity) of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8 center dot 10(-7)), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC(0-infinity) 3.9-fold; range 2.1-7.9-fold (P = 2 center dot 10(-6)), compared with ritonavir alone. Ritonavir decreased the AUC(0-4h) of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.
  • Lilius, Tuomas O.; Blomqvist, Kim; Hauglund, Natalie; Liu, Guojun; Stæger, Frederik Filip; Bærentzen, Simone; Du, Ting; Ahlström, Fredrik; Backman, Janne T.; Kalso, Eija; Rauhala, Pekka V.; Nedergaard, Maiken (2019)
    Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brainbarrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used alpha(2)-adrenergic agonist dexme-detomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.
  • Pekkinen, Minna; Saarnio, Elisa; Viljakainen, Heli T.; Kokkonen, Elina; Jakobsen, Jette; Cashman, Kevin; Mäkitie, Outi; Lamberg-Allardt, Christel (2014)