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Background: Postpartum hemorrhage remains a significant contributor to morbidity and mortality of women of childbearing age worldwide. Trends in both incidence and severity of postpartum hemorrhage are increasing which makes it imperative to identify drugs that could target prevention and/or treatment of these postpartum hemorrhages for women living in high, middle and low-income countries. Methods: We have reviewed current advances in the medical management of postpartum hemorrhage focusing on non-uterotonic therapy. We specifically describe the use and mechanism of action of tranexamic acid (TXA) and fibrinogen concentrate. Furthermore, we address the existing data for using these medications in postpartum hemorrhage, highlighting both strengths and limitations. Results: This review describes a new generation of medications that are promising for the prevention and/or treatment of postpartum hemorrhage. For patients at risk for significant hemorrhage, TXA has been shown to reduce intraoperative blood loss and can be given as a prophylactic agent. For the treatment of postpartum hemorrhage, early use of TXA has the potential to reduce mortality. In addition, some data exists supporting the use of fibrinogen concentrate, though more studies are required to help formulate guidelines for its use. Conclusion: A promising new approach for the management of severe postpartum hemorrhage is using medications that alter coagulation. More data are needed to describe ideal patient populations, dosing, the time of administration, and infusion rate.

Drums are subject to licensing procedures to ensure their quality, efficacy, and safety, but many drugs used to treat children in hospital are either not licensed for use in children [...]

CYP3A5, MDR1(ABCB1), and OATP1(SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5A6986G, ABCB1(C3435T and G2677T), and SLCO1B1(T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children.

Currently, therapeutic drug monitoring (TDM) of antiretroviral therapy (ART) is not performed in the United States as part of routine clinical care of an HIV-infected adolescent patient. TDM is recommended to rule out subtherapeutic drug concentrations and to differentiate among malabsorption, drug interactions, poor adherence, or increased drug metabolism or clearance as possible causes of decreased drug exposure. The use of TDM is also considered to assist in finding the optimal dose of a drug in patients whose virus has shown reduced susceptibility to that drug. The dosing of antiretroviral (ARV) drugs in adolescent patients with HIV infection depends on the chronologic age, weight, height, and the stage of sexual maturation. As a result of the limited data on the pharmacokinetics of ART during puberty, the transition of a dosing regimen from higher pediatric (weight and surface-based) to adult (fixed) range is not well defined. Developmental pharmacokinetic differences contribute to high variability in pediatric and adolescent patients and an increased frequency of suboptimal ARV exposure as compared to in adults. Individualized, concentration-targeted optimal dosing of ARV medications can be beneficial to patients for whom only limited dosing guidelines are available. This article describes three cases of the application of TDM in treatment-experienced adolescent patients whose ART was optimized using ARV TDM. TDM of ARV drugs is useful in managing the pharmacotherapy of HIV in adolescent patients and is well received by the adolescent patients with HIV and their families. Among others, the benefits of TDM provide evidence for adherence interventions and create grounds for enhanced education of the adolescent patient and involved adult caregivers about ART. Finally, TDM in adolescents provides valuable information about the clinical pharmacology of ART during puberty.

Compared with phase I isoenzymes, data on isoenzyme-specific phenotypic activity of uridine diphosphate glucuronosyltransferase (UGT) and its covariates in neonates are limited. In vivo observations on morphine, paracetamol (acetaminophen), and propofol disposition throughout childhood confirm the overall low-glucuronidation activity in neonates observed in in vitro studies. In addition to the phenotypic low-glucuronidation activity, in vivo observations of bilirubin (UGT1A1), morphine (UGT2B7), paracetamol (UGT1A6), and propofol (UGT1A9) glucuronidation in neonates display extensive interindividual variability, only in part explained by postmenstrual and postnatal age. Covariates like disease state characteristics (decreased morphine metabolism during therapeutic head cooling), genetic polymorphisms (UGT1A1 genetic variants and differences in bilirubin metabolism), or environmental factors (increased urinary excretion of paracetamol-glucuronide by repeated administration of paracetamol) further contribute to this variability. A focused approach to unveil covariates of the interindividual range is needed to improve our knowledge on drug disposition in early life.

To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eighty-six 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r−0.69 and −0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (Fvalue 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R20.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivoontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population.

The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods. When investigating the role of PGt factors on treatment effect, all features that influence drug response must be taken into account. Yet, PGt often has a privileged status in research protocols, with PGt factors evaluated independently from other determinants of response, instead of being regarded as other demographic or clinical covariates (e.g., age, renal function). At present, guidelines to incorporate PGt findings into label statements are lacking in part because this is a new and incompletely understood area. This situation is no longer acceptable. To achieve the potential that PGt can offer to drug development and ultimately to drug prescription, academia, industry and regulatory agencies need to pool resources on the revision of study design and data analysis requisites, bringing in model-based methodologies to enable accurate interpretation of results and provide appropriate labelling recommendations.

Aminoglycosides and glycopeptides are almost exclusively eliminated by renal excretion. Postmenstrual age (PMA) is the best predictor of their clearance, presumably because it predicts the time course of development of the glomerular filtration rate (GFR). Intrauterine growth restriction has an impact on the normalized weight of the kidney, on the number of nephrons, on GFR, and on tubular function in human perinatal life. We investigated whether prenatal growth also affects clearance of drugs such as aminoglycosides or glycopeptides that are eliminated through the kidney. Observations collected in two population pharmacokinetic studies involving preterm neonates and investigating amikacin and vancomycin in the first month of postnatal life were used to estimate the impact of prenatal growth (as judged by birth weight for gestational age) on the clearance of these drugs. Data from 1212 drug measurements (vancomycin, 648; amikacin, 564) in 531 subjects (vancomycin, 249; amikacin, 282) were available for study. Neonates born small for gestational age (SGA) were found to have a 16.2% (coefficient of variation, 12.2%) reduction in drug clearance. This effect was present from birth up to the postnatal age of 4 weeks. The covariate size (weight0.75) explained 47.3% of drug clearance; PMA, 25.2%; coadministration of a nonselective cyclo-oxygenase inhibitor, 3.5%; renal function, 7.6%; and SGA, 1.7%. Renal drug clearance is significantly lower in preterm neonates born SGA than in appropriate-for-gestational-age (AGA) controls. This reduced clearance was observed not only at birth but also up to the postnatal age of 4 weeks.

The intravenous 14C-erythromycin breath test (EBMT) has been largely used in adults as a validated probe to measure hepatic cytochrome P450 3A4 and 3A5 (CYP3A4/5) activity in vivo. Additionally, the oral EBMT has been suggested to measure combined hepatic and intestinal CYP3A4/5 activity. Both hepatic and intestinal CYP3A4/5 activities are low in neonates, but the exact developmental pattern is not known. Also, a knowledge gap exists on the impact of comedication or disease state on CYP3A4/5 activity in this population. However, to use the radioactive test in newborns is not feasible, for obvious ethical reasons. Hence, the aim of this pilot study was to determine if stable isotope-labeled 13C-erythromycin could be used alternatively. Preterm infants who needed treatment with erythromycin for ureaplasma infection were given an oral 10 to 15 mg/kg 13C-(N-dimethyl)-erythromycin dose. Pharmacy regulations did not permit intravenous administration. Exhaled air samples were collected predose and up to 24 hours post-dose and analyzed for 13CO2and 12CO2with gas chromatography-mass spectrometry. Three patients received oral 13C-erythromycin. 13CO2did not change significantly from baseline, showed a maximum blood concentration at 20 hours (+12%), and decreased over 24 hours (−16%) in these patients, respectively. Because none of these patients showed a consistent peak in 13C enrichment, in accordance with maximum blood concentration of oral erythromycin in preterms, we stopped this pilot trial after 3 patients. In conclusion, the lack of a consistent change in exhaled 13CO2after oral 13C-erythromycin in this pilot study precludes the routine use of oral 13C-EBMT in preterm infants as a noninvasive probe of CYP3A4/5 activity. We speculate that this lack of change is due to developmentally low intestinal and hepatic CYP3A activity.

The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since the introduction of NVP as part of the preferred first-line antiretroviral regimen for human immunodeficiency virus (HIV)-infected children in resource-limited settings. Adequate trough concentrations of NVP predict successful therapy, whereas subtherapeutic levels are correlated with virologic failure and development of resistance. The aim of this study was to determine the extent of agreement between total and free plasma NVP concentrations and nonstimulated saliva NVP concentrations and to evaluate the feasibility of saliva sampling as an alternative tool for therapeutic drug monitoring of NVP in children.

Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-β-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants.

The aim of the study was to study a possible pharmacokinetic-pharmacodynamic (PK-PD) relationship for midazolam in pediatric intensive care patients and to determine how adequate sedation could be reached using the COMFORT® scale as sedation scale. Twenty-one pediatric intensive care patients (2 days to 17 years) received a midazolam infusion (0.05-0.4 mg/kg/h, 3.8 hours to 25 days). Sedation levels were determined using the COMFORT scale as well as plasma concentrations of midazolam and metabolites. An evident PK-PD relationship was not found. In 20 of the 21 patients midazolam dosing could be effectively titrated to the desired level of sedation, assessed by the COMFORT scale. Based on our findings that there is no relationship between pharmacokinetic parameters and pharmacodynamic outcome, we recommend that midazolam dosing should be titrated according to the desired clinical effect in combination with a validated assessment instrument, eg, the COMFORT scale.

Combined antiretroviral therapy can reduce the transmission of human immunodeficiency virus (HIV) to an unborn child to less than two percent. An HIV-infected woman of childbearing age and her medical provider are in the unique position of making treatment decisions that not only will impact the woman’s health but also that of her child. Treatment recommendations for pregnant women infected with HIV state that therapies of known benefit to women should not be withheld during pregnancy, unless there are known adverse effects for the mother and fetus, and these adverse effects outweigh the benefit for the women. However, the recommendations of antiretroviral drugs for the treatment of HIV-infected pregnant women are subject to unique considerations, including potential changes in dosing requirement resulting from physiologic changes associated with pregnancy, and potential adverse effects on the development of the fetus and/or newborn. Currently there is a general lack of pharmacokinetic data in pregnant HIV-infected women. The limited available information suggests that pregnant women may be exposed to subtherapeutic drug levels of certain antiretroviral agents during the later stages of pregnancy, which can lead to the failure of virologic suppression, development of resistance and increased risk of vertical transmission of HIV infection. The available pharmacokinetic data regarding the use of antiretroviral therapy in pregnancy is reviewed.

Nonlinear mixed effects modeling (NONMEM) and nonparametric expectation maximization (NPEM2) have both been used in population modeling of tobramycin. We compared both methods for differences in population pharmacokinetic parameters in relation to error models used. Predictive performance was compared between models. A group of 470 neonates who had received tobramycin according to a gestational age (GA)–dependent dosing interval was analyzed according to a one-compartment model with NONMEM and NPEM2. Additional models were constructed where the assay error pattern in NPEM2 mimicked NONMEM residual error and vice versa. Individual pharmacokinetic parameter estimates were compared. Predictive performance was evaluated in a separate group of 61 patients. Population estimates and variation coefficients (CV) for optimal models were NONMEM Kel0.071 h−1(27), Vd0.59 L/kg (9); NPEM2 Kel0.079 h−1(42), Vd0.65 L/kg (48). Forcing NONMEM to use the NPEM2 error pattern as residual error or vice versa resulted in smaller differences in CVs of the estimates. NONMEM gave less bias (P< 0.05) than NPEM2 and comparable precision with this approach. In conclusion NONMEM and NPEM2 are dissimilar in population estimates. Differences in ranges of pharmacokinetic parameter estimates between NONMEM and NPEM2 are largely determined by the method of incorporating error patterns in both programs.

Caffeine is frequently used to treat apnea of prematurity in preterm infants. Because caffeine has a narrow therapeutic window, plasma concentrations are generally monitored weekly. It would be advantageous to monitor this therapy without blood sampling; saliva might offer this possibility. Paired plasma–saliva and saliva–saliva observations were made in preterm infants (n 140, gestational ages between 24 and 34 weeks) who received caffeine for the treatment of apnea of prematurity. Three methods were used to collect saliva no stimulation, dilute citric acid on collection gauze, and dilute citric acid in the cheek pouch before collection. Plasma and saliva caffeine concentrations were determined using high-performance liquid chromatography (HPLC). For all collection methods, the plots of the plasma/saliva outcomes showed linear relationships. The correlation between caffeine concentration in plasma and saliva and the reproducibility of saliva sampling was better with stimulation of saliva production using citric acid in the cheek pouch (r0.89) than with no stimulation (r0.68) or with stimulation using citric acid on the collection swab (r0.79). Monitoring of caffeine therapy in saliva can be applied reliably for routine use in clinical practice, but its reliability and reproducibility depend on the saliva sampling method used; saliva stimulation with citric acid in the cheek pouch is the best method studied.

Antimicrobial agents are the most frequently used drugs in neonatal intensive care units because bacterial infections continue to be a major cause of morbidity and mortality in preterm infants admitted to these units. This extensive use of antibiotics underscores the necessity to perform pharmacokinetic and pharmacodynamic studies in this unique patient population which will lead to optimal therapy and minimize drug-related toxicity and cost of therapy. It is apparent that maturation of organ-system function and changes in body composition during gestation, and during the neonatal period, have a significant effect on the disposition of drugs. Previous or concomitant exposure to other drugs, hypoxaemia or the severity of the pathological status of the infant may further influence drug disposition. This review presents the information currently available on the clinical pharmacokinetics of antibacterial agents in the pre-term infant. The ontogeny of the disposition of each drug is reviewed, and the currently recommended dosage regimens are given. Possible alternative dosing regimens are provided which take into account developmental changes and their impact on drug disposition. It is emphasized that prospective evaluations are needed to validate these proposed alternative dosing regimens.

The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 ± 1.13 h versus3.85 ± 0.40 h) and serum trough concentrations (46 ± 14 mg/L versus23 ± 7 mg/L) of CAZ were significantly (p< 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 ± 25.1 mL/h versus205.7 ± 55.4 mL/h), CAZ clearance per kg (40.9 ± 6.1 mL/h/kg versus60.8 ± 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 ± 0.43 versus4.73 ± 0.89) were significantly (p< 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.

The effects of gestational age (GA), body weight, and prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate (GFR) on d 3 of life in preterm infants were studied. GFR measurements were performed in 147 preterm infants with a GA between 23.4 and 37.0 wk by means of the continuous inulin infusion technique. Mean GFR values increased significantly with GA (r= 0.60, p< 0.001) and with body weight (r= 0.44, p< 0.001). Multivariate analysis indicated that GA was the most important determinant for this increase. Prenatal exposure to indomethacin resulted in significantly lower GFR values (-0.15 ± 0.03 mL/min, p< 0.001) at d 3 after birth. Prenatal administration of betamethasone and indomethacin significantly (p< 0.001) increased the GFR in comparison with exposure to indomethacin alone to levels not different than those seen in patients who were not prenatally exposed to betamethasone or indomethacin. GFR measurements were repeated in 40 preterm infants on d 10 after birth. During this 7-d period, a significant increase in GFR values (0.17 ± 0.03 mL/min, p< 0.001) was detected. This postnatal increase in GFR values was independent of GA and was not influenced by prenatal exposure to betamethasone or indomethacin. We conclude that prenatal exposure to betamethasone or indomethacin exerts significant effects on the renal function of preterm infants in the first days of life. (Pediatr Res36: 578–581, 1994)