Ronen Loebstein

Pharmacokinetic Changes During Pregnancy and Their Clinical Relevance

SummaryThe dynamic physiological changes that occur in the maternal-placental-fetal unit during pregnancy influence the pharmacokinetic processes of drug absorption, distribution and elimination. Pregnancy-induced maternal physiological changes may affect gastrointestinal function and hence drug absorption rates. Ventilatory changes may influence the pulmonary absorption of inhaled drugs.As the glomerular filtration rate usually increases during pregnancy, renal drug elimination is generally enhanced, whereas hepatic drug metabolism may increase, decrease or remain unchanged. A mean increase of 8L in total body water alters drug distribution and results in decreased peak serum concentrations of many drugs. Decreased steady-state concentrations have been documented for many agents as a result of their increased clearance.Pregnancy-related hypoalbuminaemia, leading to decreased protein binding, results in increased free drug fraction. However, as more free drug is available for either hepatic biotransformation or renal excretion, the overall effect is an unaltered free drug concentration. Since the free drug concentration is responsible for drug effects, the above mentioned changes are probably of no clinical relevance. The placental and fetal capacity to metabolise drugs together with physiological factors, such as differences acid-base equilibrium of the mother versus the fetus, determine the fetal exposure to the drugs taken by the mother.As most drugs are excreted into the milk by passive diffusion, the drug concentration in milk is directly proportional to the corresponding concentration in maternal plasma. The milk to plasma (M : P) ratio, which compares milk with maternal plasma drug concentrations, serves as an index of the extent of drug excretion in the milk. For most drugs the amount ingested by the infant rarely attains therapeutic levels.

Treating allergic rhinitis in pregnancy. Safety considerations.

Allergic rhinitis affects approximately one-third of women of childbearing age. As a result, symptoms ranging from sneezing and itching to severe nasal obstruction may require pharmacotherapy. However, product labels state that medications for allergic rhinitis should be avoided during pregnancy due to lack of fetal safety data, even though the majority of the agents have human data which refute these notions. We present a systematic and critical review of the medical literature on the use of pharmacotherapy for the management of allergic rhinitis during pregnancy. Electronic databases and other literature sources were searched to identify observational controlled studies focusing on the rate of fetal malformations in pregnant women exposed to agents used to treat allergic rhinitis and related diseases compared with controls.Immunotherapy and intranasal sodium cromoglycate (Cromolyn) and beclomethasone would be considered as first-line therapy, both because of their lack of association with congenital abnormalities and their superior efficacy to other agents. First-generation (e.g. chlorpheniramine) and second-generation (e.g. cetirizine) antihistamines have not been incriminated as human teratogens. However, first-generation antihistamines are favoured over their second generation counterparts based on their longevity, leading to more conclusive evidence of safety. There are no controlled trials with loratadine and fexofenadine in human pregnancy.Oral, intranasal and ophthalmic decongestants (e.g. pseudoephedrine, phenylephrine and oxymetazoline, respectively) should be considered as second-line therapy, although further studies are needed to clarify their fetal safety. No human reproductive studies have been reported with the ophthalmic antihistamines ketorolac and levocabastine, although preliminary data reported suggest no association between pheniramine and congenital malformations. There are no documented epidemiological studies with intranasal corticosteroids (e.g. budesonide, fluticasone propionate, mometasone) during pregnancy; however, inhaled corticosteroids (e.g. beclomethasone) have not been incriminated as teratogens and are commonly used by pregnant women who have asthma.In summary, women with allergic rhinitis during pregnancy can be treated with a number of pharmacological agents without concern of untoward effects on their unborn child. Although the choice of agents in part should be based on evidence of fetal safety, issue of efficacy needs to be addressed in order to optimally manage this condition.

The safety of omeprazole during pregnancy: A multicenter prospective controlled study

OBJECTIVES Our purpose was to determine whether omeprazole use during pregnancy is associated with an increased risk of malformations, spontaneous abortions, decreased birth weight, or perinatal complications. STUDY DESIGN In a multicenter, prospective controlled study, pregnant women exposed to omeprazole during gestation were matched with controls exposed to nonteratogens and with disease-paired controls who used histamine blockers for similar indications. The primary end point was the incidence of major malformations. RESULTS One hundred thirteen pregnant women were exposed to omeprazole during pregnancy. Rates of major malformations in the omeprazole group (4%) did not differ from controls exposed to nonteratogens (2%) (P = .68, relative risk = 1.94, 95% confidence interval 0.36 to 10.36) and disease-paired controls (2.8%). Birth weight, gestational age at delivery, preterm deliveries, and neonatal complications were comparable among the three groups. CONCLUSIONS No association was found between exposure to omeprazole during the period of organogenesis and increased risk for major malformations. Exposure throughout pregnancy is not associated with increased risk of spontaneous abortions, decreased birth weight, or perinatal complications.

Meta-analytic review of the clinical effectiveness of oral deferiprone (L1).

AbstractObjective: To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone also known as L1 or, using meta-analysis of the literature. Methods: We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic. Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration or urinary iron excretion (UIE). Efficacy data had to have been reported after ≥3 months of treatment. Data were combined using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average (mg · l−1) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg · kg−1 · day−1, which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges of deferiprone dosage: ≤50 mg · kg−1 · day−1 and ≥75 mg · kg−1 · day−1. Results: Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients. After a mean of 16 months of therapy (range 6.4–36 months) with 66.4 mg · kg−1 · day−1 (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average drop in serum ferritin of 0.8 mg · l−1 was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving ≥75 mg · kg−1 · day−1 over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When studies with patients receiving lower dosage (≤50 mg · kg−1 · day−1) were included, the success rate was 45.1%. Conclusion: Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron overloaded patients. After an average of 16 months of deferiprone in doses ≥75 mg · kg−1 · day−1, most patients had a decrease in ferritine concentration.

Fetal safety of drugs used in the treatment of allergic rhinitis: a critical review.

Allergic rhinitis is the most common allergic disease. Pharmacological interventions are often not used in pregnancy because of alarming information in drug labels and patient information, even when evidence for safety exists.Low-risk therapies could include immunotherapy, intranasal sodium cromoglycate (cromolyn sodium), beclometasone, budesonide and first-generation antihistamines. In a meta-analysis examining the safety of first-generation antihistamines in pregnancy, 200 000 first trimester exposures failed to show increased teratogenic risk. Loratadine is the most studied second-generation antihistamine (with a total patient cohort of 2147 women who were exposed) and does not appear to increase the risk of major congenital malformations; however, it has not been as well studied as the earlier antihistamines. Since desloratadine is the principal metabolite of loratadine, it can be assumed that a similar safety profile would fit for desloratadine as was described for loratadine although no direct human studies have been done.Decongestants have not been conclusively proven to affect the fetal outcome and may be used for short-term relief when no other safer alternatives are available.Intranasal corticosteroids have not been associated with an increase in congenital malformations in humans. Based on efficacy and the fact that there would be little systemic absorption, they can be considered a first-line treatment over oral antihistamines, decongestants and mast cell stabilisers; however, the number of controlled trials in pregnancy is limited. Intranasal corticosteroids are associated with minimal systemic effects in adults and are the most effective therapy for allergic rhinitis. Benefit-risk considerations must, therefore, be done but favour their first-line use during pregnancy.Because fetal safety is paramount, recommendations should be based both on the safety of the drugs during pregnancy and the comparative efficacy of the agent in the treatment of the underlying condition. This review exemplifies the fact that there are many safe treatment options for the clinician when dealing with allergic rhinitis during pregnancy.

Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study.

BACKGROUND Terfenadine is a selective, nonsedative, H(1)-blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation. OBJECTIVE We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays. METHODS A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones. RESULTS One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P =.53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 +/- 582 vs 3499 +/- 617 g; P =.04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy-related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups. CONCLUSIONS On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine.

Immune function in patients with β thalassaemia receiving the orally active iron-chelating agent deferiprone

Short‐term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immunosuppression or immunodeficiency are observed during deferiprone therapy.

DEFERIPRONE-INDUCED AGRANULOCYTOSIS: A CRITICAL REVIEW OF FIVE RECHALLENGED CASES

SummaryThe most serious adverse effect of deferiprone, the first orally active iron chelator, is agranulocytosis afflicting an estimated 1.6% of patients. Among the 13 reported patients who had experienced deferiprone-induced agranulocytosis or severe neutropenia, 5 were rechallenged. We studied the onset, clinical and rechallenge course of all 5 patients in an attempt to characterise the mechanisms involved in deferiprone-induced agranulocytosis, to verify whether rechallenge in future patients is ethically justified. Deferiprone-induced agranulocytosis showed no trend of dose dependency: of all patients who had experienced agranulocytosis 23% were treated with 50 mg/kg/day, 46% with 75 to 90 mg/kg/day, and 31 % with > 90 mg/kg/day. Available data including bone marrow aspiration in some patients support the hypothesis that an early myeloid precursor is the target cell affected by deferiprone. All 5 rechallenged patients re-experienced agranulocytosis/neutropenia. The lag period to agranulocytosis/neutropenia following reinduction was significantly shorter (13.2 ± 21.7 weeks compared with 46.4 ± 14.2 weeks in the first episode; p < 0.05). All but one of the rechallenged patients re-experienced agranulocytosis or neutropenia 2 to 4 weeks following re-exposure to deferiprone, suggesting a possible immune mechanism. We found that deferiprone was oxidised in vitro by hypochlorous acid, the major neutrophil oxidant to produce a myelotoxic metabolite. This reactive species demonstrated neutrophil toxicity and a dose-dependent lymphotoxic curve. However, we found no differences in the toxicity of this reactive species to neutrophils from 2 patients with a history of deferiprone-induced agranulocytosis when compared with controls. In combination with the clinical characteristics, these results suggest a reactive metabolite-induced immune-mediated reaction. These 5 rechallenged cases ethically preclude the rechallenge of additional cases.

Risk Factors for and Long-Term Outcome of Ifosphamide-Induced Nephrotoxicity in Children † 778

Risk Factors for and Long-Term Outcome of Ifosphamide-Induced Nephrotoxicity in Children † 778