The Pharmacokinetics and Target Attainment of Antimicrobial Drugs Throughout Pregnancy: Part III Non-penicillin and Non-cephalosporin Drugs.

INTRODUCTION: Understanding the pharmacokinetics (PK) of antimicrobial drugs in pregnant women is crucial to provide effective and safe treatment. This study is part of a series that systematically reviews literature on the PK and analyzes if, based on the changed PK, evidence-based dosing regimens have been developed for adequate target attainment in pregnant women. This part focusses on antimicrobials other than penicillins and cephalosporins. METHODS: A literature search was conducted in PubMed according to the PRISMA guidelines. Search strategy, study selection, and data extraction were independently performed by two investigators. Studies were labeled as relevant when information on the PK of antimicrobial drugs in pregnant women was available. Extracted parameters included bioavailability for oral drugs, volume of distribution (Vd) and clearance (CL), trough and peak drug concentrations, time of maximum concentration, area under the curve and half-life, probability of target attainment, and minimal inhibitory concentration (MIC). In addition, if developed, evidence-based dosing regimens were also extracted. RESULTS: Of the 62 antimicrobials included in the search strategy, concentrations or PK data during pregnancy of 18 drugs were reported. Twenty-nine studies were included, of which three discussed aminoglycosides, one carbapenem, six quinolones, four glycopeptides, two rifamycines, one sulfonamide, five tuberculostatic drugs, and six others. Eleven out of 29 studies included information on both Vd and CL. For linezolid, gentamicin, tobramycin, and moxifloxacin, altered PK throughout pregnancy, especially in second and third trimester, has been reported. However, no target attainment was studied and no evidence-based dosing developed. On the other hand, the ability to reach adequate targets was assessed for vancomycin, clindamycin, rifampicin, rifapentine, ethambutol, pyrazinamide, and isoniazid. For the first six mentioned drugs, no dosage adaptations during pregnancy seem to be needed. Studies on isoniazid provide contradictory results. CONCLUSION: This systematic literature review shows that a very limited number of studies have been performed on the PK of antimicrobials drugs-other than cephalosporins and penicillins-in pregnant women.

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review.

BACKGROUND AND OBJECTIVE: Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib. METHODS: Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded. RESULTS: Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations. CONCLUSION: Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.

Pharmacokinetics and Target Attainment of Antimicrobial Drugs Throughout Pregnancy: Part I-Penicillins.

BACKGROUND AND OBJECTIVE: Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of antibiotics in pregnant women. This review is part of a series that reviews literature on the description of PK and target attainment of antibiotics in pregnant women with specific focus on penicillins. METHODS: A systematic literature search was carried out in PubMed. Articles were labelled as relevant when information on PK of penicillins in pregnant women was available. RESULTS: Thirty-two relevant articles were included, 8 of which discussed amoxicillin (with and without clavulanic acid), 15 ampicillin, 4 benzylpenicillin, 1 phenoxymethylpenicillin, and 4 piperacillin (with and without tazobactam). No studies were found on pheneticillin and flucloxacillin in pregnant women. Ten out of 32 articles included information on both Vd and CL. During the second and third trimester of pregnancy, a higher CL and larger Vd was reported than in non-pregnant women and in pregnant women during first trimester. Reduced target attainment was described in second and third trimester pregnant women. Only 7 studies reported dosing advice, 4 of which were for amoxicillin. CONCLUSION: The larger Vd and higher CL in second and third trimester pregnant women might warrant a higher dosage or shortening of the dosing interval of penicillins to increase target attainment. Studies frequently fail to provide dosing advice for pregnant women, even if the necessary PK information was available.