Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women

Aim

Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy.

Methods

Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp® software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (C_max) and oral clearances (CL/F).

Results

PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%).

Conclusions

Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.     

A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4

Aims

Pregnant women are usually not part of the traditional drug development programme. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic (p-PBPK) model to assess the likely impact of pregnancy on three model compounds, namely caffeine, metoprolol and midazolam, based on the knowledge of their disposition in nonpregnant women and information from in vitro studies.

Methods

A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp® Simulator) was used for the nonpregnant women, and this was extended to the pregnant state by applying known changes to all model components (including the gestational related activity of specific cytochrome P450 enzymes) and through the addition of an extra compartment to represent the fetoplacental unit. The uterus and the mammary glands were grouped into the muscle compartment. The model was implemented in Matlab Simulink and validated using clinical observations.

Results

The p-PBPK model predicted the PK changes of three model compounds (namely caffeine, metoprolol and midazolam) for CYP1A2, CYP2D6 and CYP3A4 during pregnancy within twofold of observed values. The changes during the third trimester were predicted to be a 100% increase, a 30% decrease and a 35% decrease in the exposure of caffeine, metoprolol and midazolam, respectively, compared with the nonpregnant women.

Conclusions

In the absence of clinical data, the in silico prediction of PK behaviour during pregnancy can provide a valuable aid to dose adjustment in pregnant women. The performance of the model for drugs metabolized by a single enzyme to different degrees (high and low extraction) and for drugs that are eliminated by several different routes warrants further study.     

Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation

Aim

The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.

Methods

Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.

Results

Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.

Conclusions

The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.     

Medication details documented on hospital discharge: cross-sectional observational study of factors associated with medication non-reconciliation

AIMS

Movement into or out of hospital is a vulnerable period for medication safety. Reconciling the medication a patient is using before admission with the medication prescribed on discharge, and documenting any changes (medication reconciliation) is recommended to improve safety. The aims of the study were to investigate the factors contributing to medication reconciliation on discharge, and identify the prevalence of non-reconciliation.

METHODS

The study was a cross-sectional, observational survey using consecutive discharges from purposively selected services in two acute public hospitals in Ireland. Medication reconciliation, potential for harm and unplanned re-admission were investigated.

RESULTS

Medication non-reconciliation was identified in 50% of 1245 inpatient episodes, involving 16% of 9569 medications. The majority of non-reconciled episodes had potential to result in moderate (63%) or severe (2%) harm. Handwritten rather than computerized discharges (adjusted odds ratio (adjusted OR) 1.60, 95% CI 1.11, 2.99), increasing number of medications (adjusted OR 1.26, 95% CI 1.21, 1.31) or chronic illness (adjusted OR 2.08, 95% CI 1.33, 3.24) were associated with non-reconciliation. Omission of endocrine, central nervous system and nutrition and blood drugs was more likely on discharge, whilst omission on admission and throughout inpatient care, without documentation, was more likely for obstetric, gynaecology and urinary tract (OGU) or respiratory drugs. Documentation in the discharge communication that medication was intentionally stopped during inpatient care was less likely for cardiovascular, musculoskeletal and OGU drugs. Errors involving the dose were most likely for respiratory drugs.

CONCLUSIONS

The findings inform strategies to facilitate medication reconciliation on discharge from acute hospital care.     

Conformity with Optimal Drug-Use Processes: Comparison between the Accreditation Canada Managing Medications Standards and the Hospital Pharmacy in Canada Report

Background:

A recent symposium on change management highlighted the relatively slow pace of change in the drug-use process. This study was undertaken to determine the degree of concordance between different sources that document levels of conformity with optimal drug-use processes.

Objective:

The primary objective was to compare aggregate national results from the Managing Medications Standards (MMS) of Accreditation Canada and results from the biennial Hospital Pharmacy in Canada survey. The secondary objective was to discuss any significant discrepancies between the 2 sources.

Methods:

In this retrospective cross-sectional study, attempts were made to pair each Accreditation Canada MMS criterion with specific results from the Hospital Pharmacy in Canada 2009/2010 Report. Average conformity per criterion from the 2010 Accreditation Canada on-site surveys was compared with conformity as documented in the Hospital Pharmacy in Canada 2009/2010 Report. A discrepancy ratio was calculated for each criterion, with ratios less than 0.80 or greater than 1.20 being considered significant.

Results:

Overall, 82 (61%) of 134 MMS criteria could be paired with results from the 2009/2010 Hospital Pharmacy in Canada survey. The average calculated discrepancy ratio (± standard deviation) between the 2 sets of results was 0.62 ± 0.29 (range 0.05 to 1.19). The average discrepancy ratios by domain were as follows: 0.49 for safely administering medications, 0.58 for accurately preparing and dispensing medications, 0.61 for working together to promote medication safety, 0.62 for carefully selecting and procuring medications, 0.69 for monitoring quality and achieving positive results, 0.71 for appropriately ordering medications and transcribing medication orders, and 0.76 for properly labelling and storing medications. For 59 criteria, there was a significant discrepancy between the 2010 MMS on-site surveys and the 2009/2010 Hospital Pharmacy in Canada survey.

Conclusion:

Nearly two-thirds of the MMS criteria could be paired with results from the Hospital Pharmacy in Canada survey, but the average discrepancy ratio of 0.62 indicates substantial discrepancies in the data collected by these 2 methods. Further studies are required to explore the reasons for such discrepancies.     

Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women

Aims

Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy.

Methods

A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration–time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS.

Results

The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19–36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23–62)% increase in clearance (CL/F) of OC during pregnancy.

Conclusion

Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women.     

Ascertaining Problems with Medication Histories

Background:

Accurate and complete medication histories are not always obtained in clinical practice.

Objective:

This qualitative research study was undertaken to explore the barriers to and facilitators of obtaining accurate medication histories.

Methods:

Individual interviews, based on a structured interview guide, were conducted with 25 patients from both inpatient and ambulatory care clinic settings. Focus groups, based on a semistructured interview guide, were conducted with pharmacists, medical residents, and nurses. Transcribed data were analyzed by forming coded units and assessing these units for emerging themes.

Results:

Major themes that emerged from the patient interviews included patient ownership of health and medication knowledge (with knowledge of medications and their side effects and how to take medications being seen as important), patient-specific strategies to improve medication histories (e.g., use of regularly updated medication lists), and suggestions for system-level facilitators to improve medication histories (e.g., centralized databases of medication histories, increased patient education regarding the use and purpose of medications). Major themes also emerged from focus groups with health care professionals, including shared responsibility for medication history-taking among all 3 health care professions, perceptions about the barriers to medication history-taking (including patients not knowing their medications and not bringing their medication lists), and suggestions to improve medication histories (e.g., educating patients to bring medication vials to hospital admissions and appointments, using a centralized computer database for medication histories).

Conclusions:

Key recommendations resulting from this study include using standardized documentation techniques for medication histories, recording of medication history information in centralized electronic databases, educating patients to bring medications to every health care visit, and establishing criteria for pharmacist referral for cases involving complex medication histories.     

Dosing and Monitoring of Methadone in Pregnancy: Literature Review

Background:

The pharmacokinetics of methadone is altered during pregnancy, but the most appropriate dosing and monitoring regimen has yet to be identified.

Objective:

To review dosing and monitoring of methadone therapy in pregnancy.

Methods:

A literature search was performed in several databases (PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews) from inception to May 2012. The search terms were “methadone”, “pregnancy”, “pharmacokinetic”, “clearance”, “metabolism”, “therapeutic drug monitoring”, and “methadone dosing”. Additional papers were identified by searching the bibliographies of primary and review articles. All English-language primary articles related to methadone pharmacokinetics in pregnancy were included. Articles not related to maternal outcomes were excluded.

Results:

The literature search yielded 1 case report and 10 studies discussing use of methadone by pregnant women. Methadone pharmacokinetics in pregnancy has been studied in 3 pharmacokinetic trials, and split dosing of methadone in pregnant women has been described in 1 case report and 3 dosing trials. Only 4 trials evaluated monitoring of methadone concentration in pregnancy. The studies included in this review confirm that methadone pharmacokinetics is altered in pregnancy and is potentially correlated with increases in maternal withdrawal symptoms. Insufficient evidence is available to warrant routine monitoring of serum methadone concentrations in pregnant women with opioid dependence.

Conclusions:

Few studies of methadone pharmacokinetics and therapeutic drug monitoring are available for pregnant women with opioid dependence. Although it is known that methadone pharmacokinetics is altered in pregnancy, there is insufficient evidence to guide dosage adjustments and serum concentration monitoring. Until further studies are available, regular follow-up of maternal withdrawal symptoms and empiric dosage adjustments throughout pregnancy are still recommended.     

Nursing,Pharmacy, and Prescriber Knowledge and Perceptions of High-Alert Medications in a Large,Academic Medical Hospital

Background:

High-alert medications pose a greater risk of causing significant harm to patients if used in error. The Joint Commission requires that hospitals define institution-specific high-alert medications and implement processes to ensure safe medication use.

Method:

Nursing, pharmacy, and prescribers were asked to voluntarily complete a 34-question survey to assess their knowledge, experience, and perceptions regarding high-alert medications in an academic hospital.

Results:

The majority of respondents identified the organization’s high-alert medications, the consequences of an error involving a high-alert medication, and the reversal agent. Most of the risk-reduction strategies within the institution were viewed as being effective by respondents. Forty-five percent of the respondents utilized a high-alert medication in the previous 24 hours. Only 14.2% had experienced an error with a high-alert medication in the previous 12 months, with 46% being near misses. The survey found the 5 rights for medication administration were not being utilized consistently. Respondents indicated that work experience or hospital orientation is the preferred learning experience for high-alert medications.

Conclusions:

This study assessed all disciplines involved in the medication use process. Perceptions about high-alert medications differ between disciplines. Ongoing discipline-specific education is required to ensure that individuals accept accountability in the medication use process and to close knowledge gaps on high-alert medications and risk-reduction strategies.     

Pharmacy-Based Medication Reconciliation Program Utilizing Pharmacists and Technicians: A Process Improvement Initiative

Background:

Pharmacists and pharmacy technicians have an opportunity to impact the quality of the medication histories and improve patient safety by ensuring accurate medication lists are obtained and complete reconciliation has occurred with the admission medication orders by owning the admission medication reconciliation process.

Objective:

To compare the quality of a pharmacy-based medication reconciliation program on admission utilizing pharmacists and technicians to the usual multidisciplinary process.

Methods:

This was a retrospective chart review process improvement study at a 186-bed tertiary care inpatient facility. Primary outcomes included both the accuracy of pre-admission medications listed and the reconciliation of those medications with admission inpatient orders. Technicians obtained patient medication histories. Pharmacists checked the technician-obtained medication histories and ensured reconciliation of those medications with admission orders.

Results:

Medication accuracy increased from 45.8% to 95% per patient (P < .001) and medication reconciliation increased from 44.2% to 92.8% (P < .001) and remained above benchmark.

Conclusion:

A pharmacy-based medication reconciliation program utilizing both pharmacists and technicians significantly increased the accuracy and reconciliation of medications on admission. These gains were maintained for the duration of the 6-month period studied and beyond per continued process improvement data collection.     

Beliefs about medicines in Dutch acenocoumarol and phenprocoumon users

Aims

Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients'' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs.

Methods

The Beliefs about Medicines Questionnaire was used to assess medication beliefs. The questionnaire was completed by new users of coumarins indicated for venous thromboembolism or atrial fibrillation. A necessity score and a concerns score were calculated for all patients. The analyses were repeated for users of antihypertensive drugs or statins (not using coumarins).

Results

Three hundred and twenty patients were included in the analysis of the beliefs about coumarins. The mean necessity score was 15.3, the concerns score 12.3 and the necessity–concerns differential 3.0. Patients with venous thromboembolism (n = 71) had higher necessity scores than patients with atrial fibrillation (n = 249; 16.8 vs. 14.9, P < 0.001). The mean necessity score in 493 users of other cardiovascular drugs was 16.1, the concerns score 13.5 and the necessity–concerns differential 2.6. The necessity score was higher in chronic cardiovascular drug users (n = 192) than in new users (n = 301; 17.9 vs. 14.9, P < 0.001).

Conclusions

Coumarin users score higher on the necessity scale than on the concerns scale, which is also the case in users of other cardiovascular drugs. Patients with atrial fibrillation have a less positive attitude towards these drugs than patients with venous thromboembolism, and could therefore benefit more from specific attention.     

Effectiveness of a medication reconciliation project conducted by PharmD students

Objectives

This study evaluated the effectiveness of a medication reconciliation program conducted by doctor of pharmacy (PharmD) students during an advanced pharmacy practice experience.

Methods

Patients admitted to medicine or surgery units at 3 hospitals were included. Students were instructed to interview each patient to obtain a medication history, reconcile this list with the medical chart, and identify and solve drug-related problems.

Results

Eleven students reconciled medications for 330 patients over 10 months and identified 922 discrepancies. The median number of discrepancies found per patient was 2, and no discrepancies were found in 25% of the cases. In cases in which discrepancies were identified, a greater number of medications had been prescribed for the patient (7.9 ± 4.0 medications compared to 5.4 ± 3.9 medications; p < 0.05). The students completed 59 interventions. Differences were found in the numbers of discrepancies and drug-related problems that different students at different sites identified (p < 0.05).

Conclusions

Pharmacy students provided a valuable service to 3 community hospitals. The students improved the quality of patient care by identifying and solving significant drug-related problems, identifying drug allergy information, and resolving home and admission medication discrepancies.     

Modified renal function in pregnancy: impact on emtricitabine pharmacokinetics

Aims

The aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy.

Methods

FTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3.

Results

FTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5 l h⁻¹, P < 0.001), reflecting a modified renal function. FTC daily exposures (AUC) during pregnancy were lower than AUC in non-pregnant women, regardless of the trimester of pregnancy. FTC AUC geometric means were 8.38 mg l⁻¹h in the second trimester of pregnancy, 8.16 mg l⁻¹h in the third trimester of pregnancy, 8.30 mg l⁻¹h on the day of delivery and 9.77 mg l⁻¹h in non-pregnant women. FTC concentrations 24 h after administration were lower in pregnant women compared with non-pregnant women (0.054 vs. 0.079 mg l⁻¹, P < 0.001) but still above the inhibitory concentration 50%.

Conclusions

FTC CL/F was increased by 18% during pregnancy, reflecting a modified renal function with 50% increase in estimated glomerular filtration rate. However, the impact of this modified renal function on FTC pharmacokinetics was not sufficiently large to consider dose adjustments during pregnancy.