Background 
Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy.
Methods and Findings 
Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown.
Conclusion 
This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

/pdf/pregnancy-associated-changes-in-pharmacokinetics-a-wxd5cgyxtm.pdf

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review.

The pharmacokinetics of dipyrone are characterised by rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA), which has 85% bioavailability after oral administration in tablet form, and takes a short time to achieve maximal systemic concentrations (tmax of 1.2 to 2.0 hours). Absolute bioavailability after intramuscular and rectal administration is 87 and 54%, respectively. MAA is further metabolised with a mean elimination half-life (t1/2) of 2.6 to 3.5 hours to 4-formyl-amino-antipyrine (FAA), which is an end-metabolite, and to 4-amino-antipyrine (AA), which is then acetylated to 4-acetyl-amino-antipyrine (AAA) by the polymorphic N-acetyl-transferase (t1/2 of AA is 3.8 hours in rapid acetylators and 5.5 hours in slow acetylators). Urinary excretion of these 4 metabolites accounts for about 60% of the administered dose of dipyrone. Protein binding of the 4 main metabolites is less than 60%. The volume of distribution of MAA is about 1.15 L/kg of lean body mass. All 4 metabolites are excreted into breast milk. A single-dose study (0.75, 1.5 and 3g) and a multiple-dose study (1g 3 times a day for 7 days) revealed nonlinear pharmacokinetics consistent with a shift of MAA metabolism from FAA to AA. Apparent MAA clearance decreased by 22% during multiple administration. MAA clearance was reduced by 33% in the elderly. In patients with cirrhosis of the liver, the apparent clearance of all metabolites is generally reduced. In patients with renal disease, apparent clearance of MAA remains unchanged, whereas elimination of the renally excreted metabolites AAA and FAA is markedly impaired. No clinically important drug interactions have thus far been recognised. Dipyrone does not affect the pharmacodynamic response to alcohol (ethanol), glibenclamide (glyburide), oral anti-coagulants or furosemide (frusemide). The low toxicity of dipyrone and its efficacy support its use in clinical practice, despite some complex aspects of its disposition.

Clinical pharmacokinetics of dipyrone and its metabolites

Guidelines for endoscopy in pregnant and lactating women

Any drug given to a pregnant woman must be considered as possibly harmful to the fetus, since all drugs administered to the mother cross the placental membrane, although at different rates. Important physiological changes occur in pregnancy, which may influence the kinetics of drugs. Differences in gastrointestinal function are likely to alter drug absorption rates in the stomach or gut. Ventilatory alterations modify pulmonary drug absorption or elimination. Important changes in haemodynamics and alterations in body water compartments influence drug distribution and elimination. Renal drug elimination is generally enhanced, whereas hepatic drug elimination may be modified in different ways.

Drug Kinetics in Pregnancy

ASGE Guideline: Guidelines for endoscopy in pregnant and lactating women.

Each of nine nursing mothers received one single intramuscular injection of 50 mg pethidine (Dolcontral), between the third and eighth days from childbirth. The highest pethidine concentration, 0.526 mumol/l or 0.13 microgrms/ml, was recorded from breast milk, two hours from application. After 24 hours, the concentration had dropped to 0.081 mumol/l or 0.02 microgram/ml. - The milk-serum quotient was in excess of 1.0. A correlation was found to exist between pethidine concentrations in the serum, on the one hand, and those in mother's milk, on the other. - One single application of Dolcontral is not expected to be of harmful effect on the newborn.

[Excretion of pethidine in mother's milk (author's transl)].

Placental passage of sodium salicylate

Pharmacokinetic parameters may be influenced by pregnancy and labour. A number of antibiotics and chemotherapeutics were studied by the authors who found reduction of fictitious initial concentration as well as increase of both volume of distribution and total clearance. Elimination half-life was found to be prolonged with significance only in women in labour (ampicillin). Studies into drug concentrations and their metabolites did not provide any evidence to change of biotransformation in gravidity. Doses of antimicrobially acting chemopharmaceuticals in gravidity should be close to upper limits.

Pharmacokinetics of antibiotics and sulfanilamides in pregnancy and labor

The pharmacokinetics of certain drugs were studied in the following patient groups: in women in stage III of pregnancy, in women in labor, and in non-pregnant women as a control group. In late gravidity several parameters of distribution and elimination change. Nevertheless, it is not necessary to modify the usual dose schedule. However, sulfonamides and antibiotics should be administered in the upper range of dosage. In contrast to late pregnancy, we found elimination of drugs to be always retarded during labor. Attention must be paid to accumulation, which may occur.

Pharmacokinetics during pregnancy and delivery.

Strokes cause an estimated annual health care burden of 170 billion euros across Europe. Atrial fibrillation is one of the major risk factors for stroke and increases the individual risk 4.2-fold. But prevention with anticoagulants may reduce this risk by 70%. Screening methods are employed to detect previously undetected atrial fibrillation. Screening studies in various European countries show a high degree of undetected atrial fibrillation. This study aims to assess the cost-effectiveness of systematic screening with a smartphone application, named Preventicus Heartbeats. It is a hands-on screening tool for use on smartphone to diagnose AF with high sensitivity and specificity.A previously published model for calculating screening cost-effectiveness was extended to 6 European countries covering a wide range in terms of treatment costs and epidemiologic parameters.The use of screening lowers the cost per case in countries with comparatively high levels of health care costs (Switzerland: -€75; UK: -€7). Moderate higher costs per case were observed in 4 countries (Greece: €6; Netherlands: €15). Low levels of health care costs result in less or no potential for further cost reduction (Poland: €20; Serbia: €33). In all countries considered, the model showed an increase in effectiveness measures both in the number of strokes avoided and the quality adjusted life years. The number of strokes avoided per 1000 participants ranged from 2.52 (Switzerland) to 4.44 (Poland). Quality-adjusted life-years per case gained from screening ranged from 0.0105 (Switzerland) to 0.0187 (Poland). The screening procedure dominated in two countries (Switzerland, UK). For the remaining countries, the incremental cost effectiveness ratio ranged from €489/QALY (Greece) to €2548/QALY (Serbia).The model results showed a strong dependence of the results on the country-specific costs for stroke treatment. The use of the investigated screening method is close to cost-neutral or cost-reducing in the Western European countries and Greece. In countries with low price levels, higher cost increases due to AF screening are to be expected. Lower costs of anticoagulation, which are expected due to the upcoming patent expiry of direct anticoagulants, have a positive effect on the cost result. 

/pdf/cost-effectiveness-of-a-photopethysmographic-procedure-for-2e0p7l7j.pdf

Cost-effectiveness of a photopethysmographic procedure for screening for atrial fibrillation in 6 European countries

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