Identification of Medication-Related Risks in Bariatric Surgery Patients by Performing Structured Medication Reviews.

PURPOSE: More medication-related issues are seen with the growing demand for bariatric surgery, because of possible altered pharmacokinetics after surgery. Collaboration with a pharmacist could improve the short- and long-term safety and efficacy of pharmacotherapy in patients undergoing bariatric surgery. The aim of this study was to evaluate the impact of a structured medication review to identify medication-related risks before bariatric surgery. MATERIALS AND METHODS: The impact on pharmacy-led interventions of introducing a structured medication review was evaluated in a historically controlled study. In the retrospective part, we evaluated patient characteristics, medication use, and number of pre-surgery consultations with a pharmacist before the introduction of medication reviews. A flowchart was developed to detect the use of medicines with risks associated with bariatric surgery. In the prospective part, we evaluated pharmacy-led interventions after the introduction of structured medication reviews using the flowchart. Outcome effectiveness was measured through the number of pre-surgery pharmacy-led interventions. RESULTS: Before using the flowchart for screening on risk medicines, 40 (2.6%) pharmacy-led interventions were identified in 1536 patients. In the prospective group, 195 patients were included and 88 (45%) interventions were identified (p < 0.001). CONCLUSION: A structured medication review before bariatric surgery significantly increased the number of pharmacy-led interventions in bariatric surgery patients. This procedure will shift interventions to pre-surgery instead of post-surgery, contributing to the optimization of pharmacotherapy at an early stage.

Crushing lopinavir/ritonavir tablets does not result in lower exposure to lopinavir/ritonavir in adult patients with COVID-19.

OBJECTIVE: Lopinavir/ritonavir (LPV/RTV) exposure is decreased in children after crushing the tablets. Whether exposure is also decreased in adult patients is not known. This study evaluated the exposure of LPV/RTV in adult patients after administration of crushed LPV/RTV tablets. METHODS: Blood samples were drawn from patients with COVID-19 who were receiving crushed LPV/RTV 400/100 mg tablets twice daily. RESULTS: Plasma concentrations for 11 patients with COVID-19 (eight men, mean age 62.6 years) were included. The measured plasma concentrations of LPV were substantially higher than reported for patients with HIV. CONCLUSIONS: There is adequate exposure from crushed LPV/RTV tablets, but because of limited experience, therapeutic drug monitoring is still advised.

Pharmacokinetics, Short-term Safety and Efficacy of the Approved Once-daily Darunavir/Ritonavir Dosing Regimen in HIV-infected Children.

In this multicenter pharmacokinetic study in HIV-infected children (6-12 years of age), we validated the approved once-daily darunavir/ritonavir dosing recommendations. The geometric mean darunavir area under the plasma concentration-time curve was 63.1 h·mg/L, substantially lower than the mean value observed in adults. However, all trough levels were adequate, and short-term virologic outcome was good. These data support the use of the darunavir/ritonavir once-daily dosing recommendations.

In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir.

AIMS: The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated. METHODS: In vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied. RESULTS: The electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children (n = 20), was 2.4 (-8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents (n = 20) was -0.9 (-12, 9.8) mm. CONCLUSION: The palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements.

Sustained Viral Suppression in HIV-infected Children on Once-daily Lopinavir/Ritonavir in Clinical Practice.

BACKGROUND: The use of lopinavir/ritonavir once-daily (LPV/r QD) has not been approved for children. Good short-term clinical, virologic and immunologic outcomes have been observed in children on LPV/r QD. METHODS: We evaluated the long-term effectiveness of a LPV/r QD containing regimen in HIV-1-infected children in clinical practice. Selected children (0-18 years of age) with an undetectable HIV-1 RNA viral load (<50 copies/mL) for at least 6 months on a twice-daily LPV/r-containing regimen switched to LPV/r QD. The main outcome measures were the percentage of patients with an undetectable HIV-1 viral load each subsequent year after switch to LPV/r QD (on treatment and last observation carried forward), and virologic failure during follow-up (>400 copies/mL twice within 6 months). Also, the exposure to LPV on the initial once-daily dosing regimen was determined. RESULTS: Forty children (median age: 6.5 years; range: 1.0-17) were included. Median follow-up was 6.3 years (range: 1.0-10.3). During yearly follow-up, the percentage of children with an undetectable viral load varied between 82% and 100% (on treatment) and 83% and 93% (last observation carried forward). Five children (12.5%) met the criteria for failure. CD4+ and CD8+ counts remained stable at normal values. Geometric mean LPV area under the plasma concentration-time curve (linear up-log down method) over a dosing interval from time 0 to 24 hours after dosing was 169.3 mg x h/L, and last observed drug concentration was 1.35 mg/L. Adverse events were encountered in 8 patients, were mainly gastrointestinal, and in these cases, no reason to stop treatment. CONCLUSION: A once-daily LPV/r-containing regimen in HIV-1-infected children with intensive clinical and therapeutic drug monitoring is well tolerated and has good long-term clinical, virologic and immunologic outcomes.

Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis.

AIM: The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC0-24h ) is not reached. METHODS: Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4-18 years, body weight 3.4-60.5 kg); 2061 samples (median 12 per child); daily oral dose 60-300 mg (3.9-17.6 mg kg-1 )]. Steady state AUC0-24h was calculated per individual (adult target 8.9 mg·h l-1 ). RESULTS: A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2 l h-1 (4.2%) and 38.9 l (7.0%) for a median individual of 16.6 kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14 kg and <14 kg, respectively, the target AUC0-24h was reached. CONCLUSION: Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months-18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg-1  day-1 if the adult target for AUC0-24h is aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed.

The role of formulation on the pharmacokinetics of antiretroviral drugs.

INTRODUCTION: A multitude of antiretroviral drug formulations are now available for HIV-infected adults and children. These formulations include individual and co-formulated drugs, many of which are also supplied in generic versions. Many antiretroviral drugs have a low aqueous solubility and poor bioavailability. Drug formulation can significantly affect bioavailability, and given the increasing number of new formulations and drug combinations, it is important to be aware that formulation can influence the pharmacokinetics of antiretroviral drugs. AREAS COVERED: This review provides an overview of studies assessing the pharmacokinetics of different antiretroviral drug formulations in adults and children, including fixed-dose combinations. For some antiretroviral drugs, differences in pharmacokinetics have been described, with largest differences in exposure when a liquid formulation is compared to a tablet or capsule formulation. Biopharmaceutical properties of antiretroviral drugs relevant to bioavailability are discussed. EXPERT OPINION: Antiretroviral drug formulations and their excipients can significantly impact drug exposure. However, this is not yet fully recognized. It is important to realize that children use different formulations than adults. Effort should be made to ensure that adequate drug exposures are achieved to treat HIV-infected children. In addition, manipulation of drug formulations may lead to differences in pharmacokinetics.

Pharmacokinetics of pediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands.

BACKGROUND: Lopinavir/ritonavir (LPV/r) pediatric tablets (100/25 mg) are approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) as part of combination antiretroviral therapy. Dosing is based on body weight bands or body surface area under FDA approval and only body surface area by the EMA. This can lead to a different recommended dose. In addition, weight band-based dosing has not been formally studied in the target population. We evaluated the pharmacokinetics (PK) of LPV/r in children, administered twice daily according to the FDA weight bands, using pediatric tablets. METHODS: Fifty-three HIV-infected children were included in the PK substudy of the Paediatric European Network for the Treatment of AIDS 18 trial (KONCERT). In this study, children were randomized to receive LPV/r twice or once daily, according to FDA weight bands. A PK assessment was performed in 17, 16 and 20 children in the 15-25 kg, ≥ 25-35 kg and >35 kg weight band, respectively, while children took the tablets twice daily. Rich sampling was performed, and PK parameters were calculated by noncompartmental analysis. Given the high percentage of Asian children, it was also tested whether there was a difference in PK parameters between Asian and non-Asian children. RESULTS: For the total group, LPV geometric mean AUC0-12, Cmax and C12 were 106.9 h × mg/L, 12.0 mg/L and 4.9 mg/L, respectively. There were no significant differences in LPV PK parameters between the weight bands. In addition, weight was not found to be associated with variability in Cmax, C12 or AUC0-12 for the LPV PK parameters. CONCLUSIONS: FDA weight band-based dosing recommendations provide adequate exposure to LPV when using LPV/r pediatric tablets.

Pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia.

BACKGROUND: Patients who remain comatose after resuscitation are treated with moderate hypothermia. Little is known about the pharmacokinetics of drugs in patients who are treated with moderate hypothermia. OBJECTIVE: We investigated the pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia in comparison to normothermic and non-resuscitated patients. SETTING: This study was performed on the ICU of a Dutch non-academic hospital. The study population consisted of nine patients in the hypothermic group and eight patients in the control group. METHOD: The resuscitated patients were cooled to a target temperature of 33 °C and rewarmed 24 h after start of cooling. Midazolam was given as continuous infusion. The control group consisted of non-resuscitated ICU-patients who were treated with midazolam as sedative. Plasma concentration-time data were collected for midazolam and its metabolites. MAIN OUTCOME MEASURE: Non-linear mixed effect modelling was used to analyze midazolam population pharmacokinetics and identify possible covariates. RESULTS: A two-compartment pharmacokinetic model best describes the data. The pharmacokinetic models of the investigated groups are not significantly different. Pharmacokinetic parameter estimates for midazolam for the hypothermic group are a body clearance (CL) of 12.6 l/h, an apparent volume of the central compartment (V1) of 19.1 l, an apparent volume of the peripheral compartment (V2) of 108 l and an intercompartmental clearance (Q) of 18.4 l/h. Estimated parameters for the control group are CL of 14.2 l/h, a V1 of 15.7 l, a V2 of 171 l and Q of 25.6 l/h. In the covariate analysis, body temperature did not significantly improve the model. CONCLUSION: We found no significant difference in the pharmacokinetics of midazolam between resuscitated patients treated with hypothermia during 24 h and the control group.

PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection.

PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: 'When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. 'What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained.