An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins

Hirota, Tomoyoshi; Fujita, Yuito; Ieiri, Ichiro

doi:10.1080/17425255.2020.1801634

Cited by 106 publications

(114 citation statements)

References 155 publications

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“…ABCB11, a primary transporter of bile salts [76], was found to be involved in the biliary excretion of statins [77]. SLCO1B1 and SLCO1B3 are responsible for the uptake of atorvastatin into hepatocytes [78, 79]. Thus, the removal of these three transporters from atorvastatin’s TET profile may increase its plasma concentration, increasing risks of ILD [78, 79].…”

Section: Resultsmentioning

confidence: 99%

Prediction of adverse drug reactions associated with drug-drug interactions using hierarchical classification

Kim¹,

Tatonetti

2021

Preprint

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Adverse drug reactions (ADRs) associated with drug-drug interactions (DDIs) represent a significant threat to public health. Unfortunately, most conventional methods for prediction of DDI-associated ADRs suffer from limited applicability and/or provide no mechanistic insight into DDIs. In this study, a hierarchical machine learning model was created to predict DDI-associated ADRs and pharmacological insight thereof for any drug pair. Briefly, the model takes drugs' chemical structures as inputs to predict their target, enzyme, and transporter (TET) profiles, which are subsequently utilized to assess occurrences of ADRs, with an overall accuracy of ~91%. The robustness of the model for ADR classification was validated with DDIs involving three widely prescribed drugs. The model was then applied for interstitial lung disease (ILD) associated with DDIs involving atorvastatin, identifying the involvement of multiple targets, enzymes, and transporters in ILD. The model presented here is anticipated to serve as a versatile tool for enhancing drug safety.

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Section: Resultsmentioning

confidence: 99%

Prediction of adverse drug reactions associated with drug-drug interactions using hierarchical classification

Kim¹,

Tatonetti

2021

Preprint

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“…A recent review of statin pharmacokinetic and pharmacogenomic DDIs only concentrated on the metabolic processes for fluvastatin. 19 An alternate drug classification system developed by Pfizer, the Extended Clearance Classification System (ECCS), 2 attempts to predict the dominant rate-determining clearance mechanism of drugs and is based upon permeability, molecular weight, and drug ionization. Per the ECCS, high permeability acidic/zwitterionic substrates with high molecular weight (>400 daltons), such as fluvastatin, are ECCS class 1B drugs, and although they are primarily metabolized, metabolism is rate-limited by hepatic drug uptake via OATP transporters.…”

Section: Articlementioning

confidence: 99%

“…reported again a 1.9‐fold increase in fluvastatin AUC for the 80 mg extended‐release formulation of fluvastatin in patients who undergo renal transplants receiving cyclosporine vs. healthy controls. A recent review of statin pharmacokinetic and pharmacogenomic DDIs only concentrated on the metabolic processes for fluvastatin 19 …”

mentioning

confidence: 99%

Effects of Single Dose Rifampin on the Pharmacokinetics of Fluvastatin in Healthy Volunteers

Xiang

Okochi

Kozachenko

et al. 2021

Clin Pharma and Therapeutics

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The objective of this study was to determine the effects of the OATP inhibitor rifampin on pharmacokinetic of Biopharmaceutics Drug Disposition Classification System Class 1 compound fluvastatin. A crossover study was carried out in 10 healthy subjects who were randomized to 2 phases to receive fluvastatin 20 mg orally alone and following a 30‐minute 600 mg i.v. infusion of rifampin. The results demonstrated that i.v. rifampin increased the mean area under the plasma fluvastatin concentration–time curve (AUC0–∞) by 255%, mean peak plasma concentration (Cmax) by 254%, decreased oral volume of distribution by 71%, whereas the mean elimination terminal half‐life (T1/2), mean absorption time (MAT), and time to peak concentration (Tpeak) of fluvastatin did not significantly change. The study demonstrated that rifampin exhibited a significant drug interaction with fluvastatin. The mechanism of the increased plasma concentrations is likely due to inhibition of OATP transporters in hepatocytes.

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“…Serial blood samples were collected in dipotassium ethylenediaminetetraacetic acid-containing collection tubes to determine plasma concentrations of upadacitinib and rosuvastatin and sodium heparincontaining collection tubes to determine the plasma concentrations of atorvastatin and orthohydroxyatorvastatin. For rosuvastatin, samples were collected starting on day 1 of period 1 and day 7 of period 2 at 0 (before dosing), 0.5, 1, 2, 3,4,5,6,8,11,15,23,36,48,72, and 96 hours after dosing rosuvastatin. For the atorvastatin and ortho-hydroxyatorvastatin, samples were collected starting on day 1 of period 1 and day 7 of period 2 at 0 (before dosing), 0.5, 1, 1.5, 2, 3,4,6,8,11,15,23,36,48,72, and 96 hours after dosing atorvastatin.…”

Section: Pharmacokinetic Sampling and Bioanalysismentioning

confidence: 99%

Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects

Mohamed

Coppola

Tian

et al. 2021

Clinical Pharm in Drug Dev

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This phase 1, 2-part, 2-period, open-label, drug-drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once-daily doses of upadacitinib extended-release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to infinity (AUC inf ) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin C max and AUC inf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The C max and AUC inf of the active metabolite ortho-hydroxyatorvastatin remained unchanged. Administration of a single 5-mg dose of rosuvastatin or a single 10-mg dose of atorvastatin had no relevant effect on upadacitinib C max or area under the plasma concentrationtime curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.

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An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins

Cited by 106 publications

References 155 publications

Prediction of adverse drug reactions associated with drug-drug interactions using hierarchical classification

Prediction of adverse drug reactions associated with drug-drug interactions using hierarchical classification

Effects of Single Dose Rifampin on the Pharmacokinetics of Fluvastatin in Healthy Volunteers

Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects

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