A clinician's guide to statin drug-drug interactions

Kellick, Kenneth; Bottorff, Michael B.; Tóth, Peter P.

doi:10.1016/j.jacl.2014.02.010

Cited by 124 publications

(85 citation statements)

References 31 publications

(32 reference statements)

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“…Consistent with in vitro and clinical drug-drug interaction findings to date (1,(5)(6)(7), data from the current investigation support the hypothesis that doravirine does not have a clinically meaningful effect on CYP3A4 metabolism or OATP1B1, MDR1, and BCRP transporters, which are implicated in the disposition of atorvastatin (13,14). This observation was justified by the lack of changes in exposure, clearance, and half-life associated with atorvastatin when it was administered both alone and concomitantly with doravirine.…”

Section: Discussionsupporting

confidence: 87%

“…3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are a mainstay in treatment, with atorvastatin being a commonly prescribed agent. Atorvastatin undergoes hepatic metabolism and is a substrate of the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1); P-glycoprotein (P-gp), also known as multidrug resistance protein 1 (MDR1); and BCRP (13,14). Similarly to doravirine, atorvastatin is metabolized by CYP3A4 (13), and CYP3A4 modulators have demonstrated a marked effect on its pharmacokinetics (PK) (15).…”

mentioning

confidence: 99%

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Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Khalilieh

Yee

Sánchez

et al. 2017

Antimicrob Agents Chemother

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Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirineatorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Khalilieh

Yee

Sánchez

et al. 2017

Antimicrob Agents Chemother

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“…8,21,33,34 Attention to these factors may be the best way to minimise the risk of muscle injuries, which are reported with all marketed statins. 33 The highest risk of developing an SaMAE is with 80 mg of simvastatin (18.2%); therefore, this dose is better avoided.…”

Section: Risk Factorsmentioning

confidence: 99%

“…35,36 Drug interactions vary with statin type and dose; specific statin-drug interactions and contraindications have been previously reviewed in more detail. 34 …”

Section: Risk Factorsmentioning

confidence: 99%

Statin-Associated Muscle Adverse Events: Update for clinicians

Al-Mohaissen¹,

Ignaszewski²,

Fröhlich³

et al. 2016

SQUMJ

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Statins are potent medications which reduce low-density lipoprotein cholesterol (LDL-C) levels. Their efficacy in cardiovascular risk reduction is well established and indications for their use are expanding. While statins are generally well tolerated and safe, adverse events are relatively common, particularly statinassociated muscle adverse events (SaMAEs), which are the most frequently encountered type of adverse event. Recent guidelines and guideline updates on SaMAEs and statin intolerance have included revised definitions of SaMAEs, incorporating new evidence on their pathogenesis and management. As SaMAEs emerge as a therapeutic challenge, it is important for physicians to be aware of updates on management strategies to ensure better patient outcomes. The majority of patients who are considered statin-intolerant can nevertheless tolerate some forms of statin therapy and successfully achieve optimal LDL-C levels. This review article discusses the recent classification of SaMAEs with emphasis on pathogenesis and management strategies.

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“…[8][9][10][11][12][13] For example, several haplotypes of commonly occurring genetic polymorphisms in the liver-specific organic anion-transporting polypeptide 1B1 (OATP1B1) were associated with increased blood concentrations of the non-CYP3A4-metabolized statins rosuvastatin and pravastatin in humans. [13][14][15][16] Clarithromycin has been shown to inhibit OATP1B1 and OATP1B3 in hepatocyte cell cultures.…”

mentioning

confidence: 99%