Negative impact of a health insurer-mandated de-simplification from a single-tablet regimen to a two-tablet regimen.

OBJECTIVES: Antiretroviral therapy (ART) accounts for a considerable proportion of HIV care expenses. In June 2021, a Dutch healthcare insurer implemented a mandatory policy to de-simplify branded RPV/TDF/FTC (Eviplera) into a two-tablet regimen containing rilpivirine (Edurant) and generic TDF/FTC as part of cost-saving measures. The objectives of this study were to evaluate the acceptance of this policy, the trends in ART dispensation, and cost developments. DESIGN: A retrospective database study. METHODS: In this study, medication dispensation data were obtained from the Dutch Foundation for Pharmaceutical Statistics (SFK). This database covers 98% of all medication dispensations from Dutch pharmacies including people with HIV who receive ART. We received pseudonymized data exclusively from individuals insured by the insurer for the years 2020-2022. Costs were calculated using Dutch drug prices for each year. RESULTS: In June 2021, 128 people with HIV were on branded RPV/TDF/FTC. Following the policy implementation, 59 (46%) had switched to RPV + generic TDF/FTC, but after 1.5 years, only 17 of 128 individuals (13%) used the proposed two-tablet regimen. The other 111/128 used RPV/TDF/FTC with prescriptions for 'medical necessity' ( n  = 29), switched to RPV/TAF/FTC ( n  = 51), or other ART ( n  = 31). Despite expectations of cost-savings, costs increased from €72 988 in May 2021 to €75 649 in May 2022. CONCLUSION: A mandatory switch from an STR to a TTR in people with HIV proved unsuccessful, marked by low acceptance, and increased costs after 1 year. This underscores the necessity of incorporating patient and prescriber involvement in changing medication policies.

Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.

BACKGROUND: Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. METHODS: We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies. RESULTS: A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and  Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target. CONCLUSIONS: A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.

The Pharmacoeconomic Benefits of Pemetrexed Dose Individualization in Patients With Lung Cancer.

Neutropenia is a dose-related treatment-limiting and costly adverse event of pemetrexed. We postulate that individualized dosing reduces the incidence of neutropenia. The aims of this study were (i) to investigate the costs of pemetrexed-related neutropenia and (ii) to determine the pharmacoeconomic benefits of individualized dosing of pemetrexed in terms of budget impact, yearly cost savings, and reduction in severe neutropenia. Retrospective data on the treatment of grade 3 or higher neutropenia during pemetrexed-based chemotherapy were collected from three Dutch hospitals to determine the mean healthcare consumption during a neutropenic episode. Subsequently, Monte Carlo simulations were performed using a validated pharmacokinetic/pharmacodynamic model to predict the neutropenia incidence during four cycles for standard dosing of pemetrexed and individualized dosing. The mean costs per neutropenia and the expected neutropenia incidence were combined to calculate the budget impact and cost savings. We found that the average costs per pemetrexed-associated neutropenic episode to be €1,490 (US $1,674). The neutropenia incidence for the standard and individualized pemetrexed dosing strategies were 12.7% and 9.9%, respectively. This resulted in total expected neutropenia-related costs of ~ €3.0 million (US $3.372 million) and €2.4 million (US $2.697 million), respectively. Taking the number of patients eligible for pemetrexed treatment into account, individualized dosing could result in saving €686,000 (US $770,995) on a yearly basis in the Netherlands alone. Individualized dosing of pemetrexed can decrease the incidence of neutropenia and thus result in a significant decrease in neutropenia-related costs and decreased risk of hospitalization or even death while maintaining therapeutic exposure.

High unbound flucloxacillin fraction in critically ill patients.

OBJECTIVES: To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies. PATIENTS AND METHODS: Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR. RESULTS: The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of >2.5 mg/L (100% fT>5×MIC, MIC = 0.5 mg/L). CONCLUSIONS: Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.

Point-of-Care Detection of Nonadherence to Antiretroviral Treatment for HIV-1 in Resource-Limited Settings Using Drug Level Testing for Efavirenz, Lopinavir, and Dolutegravir: A Validation and Pharmacokinetic Simulation Study.

BACKGROUND: Virological failure during antiretroviral treatment (ART) may indicate the presence of drug resistance, but may also originate from nonadherence. Qualitative detection of ART components using drug level testing may be used to differentiate between these scenarios. We aimed to validate and implement qualitative point-of-care drug level tests for efavirenz (EFV), lopinavir (LPV), and dolutegravir (DTG) in rural South Africa. METHODS: Qualitative performance of immunoassays for EFV, LPV, and DTG was assessed by calculating limit of detection (LoD), region of uncertainty, and qualitative agreement with a reference test. Minimum duration of nonadherence resulting in a negative drug level test was assessed by simulation of treatment cessation using validated population pharmacokinetic models. RESULTS: LoD was 0.05 mg/L for EFV, 0.06 mg/L for LPV, and 0.02 mg/L for DTG. Region of uncertainty was 0.01-0.06 mg/L for EFV, 0.01-0.07 mg/L for LPV, and 0.01-0.02 mg/L for DTG. Qualitative agreement with reference testing at the LoD in patient samples was 95.2% (79/83) for EFV, 99.3% (140/141) for LPV, and 100% (118/118) for DTG. After simulated treatment cessation, median time to undetectability below LoD was 7 days [interquartile range (IQR) 4-13] for EFV, 30 hours (IQR 24-36) for LPV, and 6 days (IQR 4-7) for DTG. CONCLUSIONS: We demonstrate that qualitative ART drug level testing using immunoassays is feasible in a rural resource-limited setting. Implementation of this technology enables reliable detection of recent nonadherence and may allow for rapid and cost-effective differentiation between patients in need for adherence counseling and patients who require drug resistance testing or alternative treatment.

The potential of individualized dosing of ravulizumab to improve patient-friendliness of paroxysmal nocturnal haemoglobinuria treatment at reduced costs.

Ravulizumab is a very expensive complement C5-inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria, with a fixed-dosing interval of 8 weeks. For lifelong treatment, a cost-effective and patient-friendly dosing strategy is preferred. We therefore explored alternative ravulizumab dosing regimens in silico based on the thorough dose-finding studies of the manufacturer. Extending the interval to 10 weeks or individually extending the interval to a mean of 12.8 weeks based on pharmacokinetic monitoring resulted in noninferior efficacy in terms of lactate dehydrogenase normalization, with drug cost savings up to 37%. We here show the potential of individualized ravulizumab dosing to improve patient-friendliness at reduced costs.

Pharmacokinetics and Generic Drug Switching: A Regulator's View.

There appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic drug use and drug switches. In this article, we describe why we are of the opinion that the current regulatory approach to the evaluation of generic drugs based on average bioequivalence is sufficient to expect therapeutic equivalence in the clinical setting. This has often been debated, specifically as adverse drug reactions related to generic drug switches are regularly reported. We agree that clinical discomfort during a bioequivalent drug switch may indeed be caused by different exposures to the active substance. However, this difference in exposure is not a result of the characteristics or quality of generic drugs; it is caused by the pharmacokinetic within-subject variability of the active substance, i.e., the variability on the bioavailability of the active substance, when comparing two occasions of administration of the same drug product, to the same patient. Therefore, reported clinical discomfort following generic drug use and drug switches does not warrant a change in the regulatory approach to the evaluation of the bioequivalence of generic drugs. Switching from a brand-name drug to currently approved generic drugs, or between different generic drugs, will in principle result in comparable exposure, within boundaries determined by the within-subject variability of the pharmacokinetics of the active substance involved.

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling.

Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual-side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (Ctrough ) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy.

Large differences in neonatal drug use between NICUs are common practice: time for consensus?

AIMS: Evidence for drug use in newborns is sparse, which may cause large differences in drug prescriptions. We aimed to investigate the differences between neonatal intensive care units (NICUs) in the Netherlands in currently prescribed drugs. METHODS: This multicentre study included neonates admitted during 12 months to four different NICUs. Drugs were classified in accordance with the Anatomical Therapeutic Chemical (ATC) classification system and assessed for on/off-label status in relation to neonatal age. The treatment protocols for four common indications for drug use were compared: pain, intubation, convulsions and hypotension. RESULTS: A total of 1491 neonates (GA range 23+6 -42+2 weeks) were included with a total of 32 182 patient days, 181 different drugs and 10 895 prescriptions of which 23% was off-label in relation to neonatal age. Overall, anti-infective drugs were most frequently used with a total of 3161 prescriptions, of which 4% was off-label in relation to neonatal age. Nervous system drugs included 2500 prescriptions of which 31% was off-label in relation to neonatal age. Nervous system drugs, blood and blood forming organs, and cardiovascular drugs showed the largest differences between NICUs with ranges of 919-2278, 554-1465, and 238-952 total prescriptions per 1000 patients per ATC class, respectively. CONCLUSIONS: We showed that drug use varies widely in neonatal clinical practice. The drug classes with the highest proportion of off-label drugs in relation to neonatal age showed the largest differences between NICUs, i.e. cardiovascular and nervous system drugs. Drug research in neonates should receive high priority to guarantee safe and appropriate medicines and optimal treatment.

Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.

BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

IMPORTANCE: New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE: To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS: Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE: After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Assessment of drug-drug interactions between tenofovir disoproxil fumarate and the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz in HIV-infected patients.

BACKGROUND: Tenofovir disoproxil fumarate (DF) has been studied in combination with efavirenz in healthy volunteers and no interaction was found. No data are available on the possible interaction of tenofovir DF with nevirapine and efavirenz in HIV-infected patients. In this study the combination of nevirapine 200 mg twice daily with tenofovir DF 300 mg once daily and nevirapine 400 mg once daily with tenofovir DF 300 mg once daily were compared with nevirapine twice daily or once daily without tenofovir DF in HIV-infected patients. Furthermore, the combination of efavirenz 600 mg and tenofovir DF 300 mg once daily was compared with use of efavirenz 600 mg once daily only. METHODS: Data were retrospectively collected from routine therapeutic drug monitoring plasma samples. Nevirapine, efavirenz, and tenofovir plasma levels and tenofovir concentration ratios were analyzed. The concentration ratio represents the measured plasma concentration compared with the time-adjusted average concentration, as measured in a reference population. Six different groups were studied: 200 mg nevirapine twice daily, 400 mg nevirapine once daily, 600 mg efavirenz once daily, all without tenofovir DF (groups 1, 2, and 3, respectively), and the same groups with the drugs combined with tenofovir 300 mg once daily (groups 4, 5, and 6, respectively). RESULTS: Plasma samples were evaluable for 272, 18, 126, 32, 94, and 118 patients in the groups 1-6, respectively. No differences were found in plasma levels for tenofovir, nevirapine, and efavirenz for either of the combinations studied. Addition of tenofovir DF to efavirenz or nevirapine in HIV-infected patients does not influence the plasma levels of nevirapine or efavirenz. Furthermore, nevirapine and efavirenz have no effect on tenofovir plasma levels or tenofovir concentration ratios. CONCLUSION: Efavirenz or nevirapine can be coadministered with tenofovir DF in HIV-infected patients without dose modifications.

Evaluation of antiretroviral therapy results in a resource-poor setting in Blantyre, Malawi.

OBJECTIVE: To evaluate treatment results of the paying antiretroviral therapy (ART) clinic of Queen Elizabeth Central Hospital, a large public and teaching hospital in Blantyre, Malawi. The only ART was a fixed drug combination of stavudine, lamivudine and nevirapine. METHODS: Cross sectional study with interviews, laboratory tests (CD4 count, viral load, nevirapine plasma levels, transaminases) and data extraction from files. RESULTS: A total of 422 (59%) of the patients who started ART since 2000 were lost to follow-up. The 176 patients enrolled in the study had good virological and excellent clinical treatment results. The most common side effect was peripheral neuropathy. Nevirapine plasma levels were remarkably high and associated with successful virological treatment results. Two simple adherence questions pertaining to the use of medication in the previous 8 days corresponded well with nevirapine levels. The most important reasons for non-adherence were shortage of drugs in the hospital pharmacy and personal financial constraints. CONCLUSIONS: (1) Many patients were lost to follow-up. (2) High nevirapine levels contributed to good therapy results in those studied. (3) Simple adherence questions predicted subtherapeutic nevirapine levels. (4) Antiretroviral drug supply needs to be uninterrupted and free of charge, to prevent avoidable non-adherence.

Assessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring.

BACKGROUND: Adherence to protease inhibitor-containing antiretroviral therapy is crucial, but difficult to measure. OBJECTIVE: To compare and combine various methods of measuring adherence to the strict protease inhibitor-containing regimens. METHODS: The following methods were used: medication event monitoring system (MEMS) caps (electronic monitoring), therapeutic drug monitoring, pill count, pharmacy refill data, questionnaires, diaries (for registration of food patterns and special events related to the use of MEMS), adherence assessment by the physician and clinical nurse specialist, and in-depth interviews. In addition, ultrasensitive viral load and resistance testing was performed. RESULTS: Twenty-eight patients were included; data could be evaluated in 26. According to MEMS data, 25% of the patients took fewer than 95% of all doses, and two thirds of the patients took fewer than 95% of the doses on time. Only 43% of the patients showed good adherence with food restrictions. Methods that showed significant correlations with MEMS results were patients' self-reported adherence; therapeutic drug monitoring, indicating plasma levels outside predefined ranges; and estimation of adherence by a clinical nurse specialist, especially by in-depth interview. CONCLUSION: Diary-corrected MEMS data gave a detailed insight into patients' adherence patterns. Patients' self-report and therapeutic drug monitoring were significantly correlated with the MEMS data, and the clinical nurse specialist may also play a role in identifying patients who are imperfectly adherent.