Interactions between pristinamycin (Pyostacine) and mirtazapine, ziprasidone or risperidone

Fråga: Are there any known pharmacological interactions between pristinamycin (Pyostacine) and mirtazapine, ziprasidone or risperidone?

Sammanfattning: Prinstinamycin could theoretically increase the exposure to mirtazapine, ziprasidone and risperidone through inhibition of CYP3A4 and p-glycoprotein. Available evidence is too scarce to recommend prophylactic dose adjustments, but the patient should be observant of concentration-dependent side effects of the three psychotropic drugs. Theoretically, the combination could increase the risk of QTc prolongation and Torsades de Pointes.

Svar: Pristinamycin belongs to a group of bacteriostatic antibiotics known as the streptogramins and is a naturally occurring mixture of two components, pristinamycin I and pristinamycin II. Pristinamycin I is a macrolide and pristinamycin II is a depsipeptide (a peptide with amide bonds replaced by ester bonds). The two components have synergistic inhibitory effects on bacterial protein synthesis (1, 2).

We found no reports of pharmacological interactions between pristinamycin and mirtazapine, ziprasidone or risperidone in Drugline, Medline or standard pharmacological literature. However, similar to conventional macrolides, pristinamycin has been reported to cause drastically increased levels of ciclosporin (3). Since ciclosporin is a CYP3A (cytochrome P450 A) substrate and documented interactions between ciclosporin and macrolides are attributed to CYP3A inhibition, it seems plausible that pristinamycin could be an inhibitor of CYP3A (3, 4). This notion gains additional support from the fact that dalfopristine, a semisynthetic pristinamycin derivative, is a known inhibitor of CYP3A4 both in vitro and in vivo (5, 6).

In addition, several macrolides inhibit the drug transporter p-glycoprotein (P-gp) and pristinamycin has been shown to inhibit this enzyme in vitro (4, 7, 8).

Mirtazapine, ziprasidone and risperidone are all partially metabolized by CYP3A4, and the latter two drugs are P-gp substrates (9, 10, 11). Hence, co-administration of pristinamycin could theoretically increase the plasma concentrations of all three drugs.

Pristinamycin itself is metabolized by the cytochrome P450 system and subsequently excreted through the bile, but there is a lack of detailed information regarding the elimination pathways involved (12). Considering the general interaction profiles of mirtazapine, ziprasidone and risperidone, it seems unlikely that these drugs would have any important effects on the pharmacokinetics or pharmacodynamics of pristinamycin (4). However, mirtazapine, ziprasidone and risperidone have all been associated with QTc prolongation, and the risk of this adverse effect could theoretically increase after addition of pristinamycin, since macrolides have a well-documented propensity to cause QTc prolongation and Torsades de Pointes (13). Mast Y, Wohlleben W. Streptogramins two are better than one! Int J Med Microbiol 2014;304(1):44-50 Hamilton-Miller JM. From foreign pharmacopoeias: new antibiotics from old? J Antimicrob Chemother 1991;27:702-5 Baxter K, Preston CL (eds), Stockley´s Drug interactions. (online) London: Pharmaceutical Press. Ciclosporin + Antibacterials; Macrolides. (cited 2014-02-04) SFINX (Swedish, Finnish INteraction X-referencing) (cited 2014-02-11) Bearden DT. Clinical pharmacokinetics of quinupristin/dalfopristin. Clin Pharmacokinet 2004;43(4):239-52 Tie Y, McPhail B, Hong H, Pearce BA, Schnackenberg LK, Ge W, Buzatu DA, Wilkes JG, Fuscoe JC, Tong W, Fowler BA, Beger RD, Demchuk E. Modeling chemical interaction profiles: II. Molecular docking, spectral data-activity relationship, and structure-activity relationship models for potent and weak inhibitors of Cytochrome P450 CYP3A4 isozyme. Molecules 2012;17:3407-3460 Eberl S, Renner B, Neubert A, Reisig M, Bachmakov I, König J, Dörje F, Murdter TE, Ackermann A, Dormann H, Gassmann KG, Hahn EG, Zierhut S, Brune K, Fromm MF. Role of p-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmacoepidemiological studies. Clin Pharmacokinet 2007;46(12):1039-49 Phung-Ba V, Warnery A, Scherman D, Wils P. Interaction of pristinamycin IA with P-glycoprotein in human intestinal epithelial cells. Eur J Pharmacol 1995;282(2):187-92

Mirtazapin. Produktresumé (SPC) (cited 2014-02-11)
Zeldox. Produktresumé (SPC) (cited 2014-02-11)
Risperdal. Produktresumé (SPC) (cited 2014-02-11)

Grayson ML, Crowe SM, McCarthy JS, Mills J, Mouton JW, Norrby SR, Paterson DL, Pfaller MA. Kucer´s The use of antibiotics. 6th ed. CRC Press 2010, p. 932 Resources for Healthcare Professionals. CredibleMeds info@azcert.org