Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.

PURPOSE: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown. METHODS: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels. RESULTS: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013). CONCLUSION: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin. CLINICAL TRIALS REGISTRATION: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy.

OBJECTIVE: To describe a hypoalbuminemic critically ill patient with subtherapeutic total valproic acid serum concentrations but unbound valproic acid concentrations within normal limits. CASE SUMMARY: During an intensive care unit admission, a 61-year-old woman with urosepsis and multiorgan dysfunction syndrome developed tonic-clonic seizures with respiratory failure, and tracheal intubation was performed. An intravenous loading dose of valproic acid 1500 mg (25 mg/kg) was administered and therapy was continued with valproic acid 750 mg (12.5 mg/kg) twice daily. Because of progressive renal failure, continuous venovenous hemofiltration was started on day 3 of valproic acid therapy. On day 7 of valproic acid therapy, routine testing of serum valproic acid trough concentration returned as undetectable. Subsequent determinations of trough serum concentrations of total valproic acid showed values below the therapeutic range. Data from a full pharmacokinetic curve (multiple blood samples during a dosing interval) showed that the free fraction of valproic acid was >60%. Although total valproic acid concentrations were still low, the unbound concentrations were considered therapeutic. Serum albumin was 1.2 g/dL on the multiple sampling day. DISCUSSION: The patient's hypoalbuminemia probably explains the remarkably high free fraction of valproic acid. Our hypothesis is that the low albumin level was associated with high plasma clearance of valproic acid, leading to extremely low total drug concentrations. To our knowledge, this high percentage of free valproic acid has not been previously described. CONCLUSIONS: Health-care professionals should be aware of the need of early determination of both total and free fraction valproic acid serum concentrations in hypoalbuminemic critically ill patients. Increasing the dose of valproic acid purely based on total valproic acid serum concentrations in this patient population should be avoided.

Practical guidelines to interpret plasma concentrations of antiretroviral drugs.

Several relationships have been reported between antiretroviral drug concentrations and the efficacy of treatment, and toxicity. Therefore, therapeutic drug monitoring (TDM) may be a valuable tool in improving the treatment of HIV-1-infected patients in daily practice. In this regard, several measures of exposure have been studied, e.g. trough and maximum concentrations, concentration ratios and the inhibitory quotient. However, it has not been unambiguously established which pharmacokinetic parameter should be monitored to maintain optimal viral suppression. Each pharmacokinetic parameter has its pros and cons. Many factors can affect the pharmacokinetics of antiretroviral agents, resulting in variability in plasma concentrations between and within patients. Therefore, plasma concentrations should be considered on several occasions. In addition, the interpretation of the drug concentration of a patient should be performed on an individual basis, taking into account the clinical condition of the patient. Important factors herewith are viral load, immunology, occurrence of adverse events, resistance pattern and comedication. In spite of the described constraints, the aim of this review is to provide a practical guide for TDM of antiretroviral agents. This article outlines pharmacokinetic target values for the HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Detailed advice is provided on how to interpret the results of TDM of these drugs.

Race is not associated with nevirapine pharmacokinetics.

The effect of race on the pharmacokinetics of nevirapine was investigated in a nonselected population. Included patients were ambulatory HIV-1-infected patients from the outpatient clinics of the Academic Medical Center and the Slotervaart Hospital, Amsterdam, The Netherlands. All patients were using nevirapine as part of their antiretroviral regimen and had at least one plasma concentration available for analysis. From the included patients, gender, age, race, hepatitis C status, baseline ASAT value, and body weight were obtained. The nonlinear mixed-effect modeling program (NONMEM) version V 1.1 was used for all analyses. Population pharmacokinetic parameters [clearance (CL/F), volume of distribution (V/F), absorption rate constant (ka)] and interindividual (IIV) and interoccasion variability (IOV) were estimated. The influence of race on the CL/F of nevirapine was tested as Negroid race versus the other races, Asian race versus the other races, and the Negroid and the Asian races as separate variables versus the Caucasian race. A database of 1732 nevirapine plasma concentrations of 383 HIV-1-infected individuals collected during 1186 outpatient clinic visits was available for this analysis. The conclusion of this study is that race is not associated with the pharmacokinetics of nevirapine, and thus requires no dose adaptations.

Incidence and risk factors for nevirapine-associated rash.

OBJECTIVE: To determine the incidence of rash in HIV-1 infected individuals starting a nevirapine-containing regimen in an unselected outpatient clinic population. Possible risk factors including plasma concentrations of nevirapine were evaluated for their relationship with the occurrence of a rash. METHODS: The occurrence of rash was extracted from the outpatient medical records or based on a prescription of the antihistaminic cetirizine as documented by the community pharmacy within the first 90 days of nevirapine use. During regular visits to the clinic blood samples were collected for the determination of nevirapine plasma concentrations. Possible risk factors such as demographics, immunology, virology, clinical chemistry and antiretroviral pretreatment were collected at baseline for each patient. In addition, concomitantly used drugs during the nevirapine-based regimen were recorded. The association between these factors and the occurrence of rash was studied. Primary outcome was the onset of rash within the first 90 days after initiation of a nevirapine-containing regimen. RESULTS: Data from 216 HIV-1-infected patients were used in this study. Thirty-eight patients (17.6%) developed a rash of some grade that led to discontinuation of nevirapine in seven patients (3.2% of the included patients). The median time to occurrence of rash was 26 days (interquartile range 17-46 days). The multivariate analysis showed that patients pretreated with antiretroviral drugs less than 12 months before the initiation of a nevirapine-containing regimen had a more than 2.5-fold increased risk of developing rash. Furthermore, nevirapine plasma concentrations were also significantly related to the occurrence of rash. A more than twofold increased risk for developing rash was observed for patients with nevirapine plasma concentrations above 5.3 mg/l. CONCLUSIONS: This is the first study demonstrating that patients with antiretroviral pretreatment less than 12 months and with nevirapine plasma concentrations above 5.3 mg/l during the first 90 days of treatment are at a higher risk for the development of rash. It is therefore advised to monitor this group of patients carefully when initiating nevirapine-containing therapy.

Subtherapeutic antiretroviral plasma concentrations in routine clinical outpatient HIV care.

The objective of this study was to evaluate plasma concentrations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) within several dosing schemes in a cohort of HIV-infected patients in routine clinical practice and to find possible explanations for subtherapeutic plasma concentrations. Patients were included if a PI or NNRTI was part of their antiretroviral regimen, at least one plasma concentration was obtained, and a complete medication overview from community pharmacy records was available. The study period was from January 1998 to September 2001. Each plasma concentration was related to median plasma concentrations of a pharmacokinetic reference curve, yielding a concentration ratio (CR). A cutoff CR was defined for each antiretroviral drug per specific regimen, discriminating between >or=therapeutic and subtherapeutic concentrations. For the patients with subtherapeutic concentrations, it was sorted out whether drug interactions, adverse events and self-reported symptoms, or nonadherence could be the cause of the lower than expected plasma concentration. Ninety-seven HIV-infected patients fulfilled the criteria. During the defined period, 1145 plasma concentrations were available (median, 11; interquartile range, 8-14). Three hundred fourteen (27.4%) plasma concentrations were classified subtherapeutic. Drug interactions (2; 0.6%), adverse events and self-reported symptoms (67; 21.3%), and nonadherence (14; 4.5%) could only partly explain the subtherapeutic drug levels. Consequently, a large number of the subtherapeutic plasma concentrations (73.6%) remained inexplicable. A high number of subtherapeutic plasma concentrations were observed. No clear causes were found; thus, corrective measures will be difficult to employ. Therefore, therapeutic drug monitoring (TDM) must maintain its crucial place in routine clinical care to be able to identify patients who need extra attention so that therapeutic plasma concentrations are achieved.

Drug interactions between antiretroviral drugs and comedicated agents.

HIV-infected individuals usually receive a wide variety of drugs in addition to their antiretroviral drug regimen. Since both non-nucleoside reverse transcriptase inhibitors and protease inhibitors are extensively metabolised by the cytochrome P450 system, there is a considerable potential for pharmacokinetic drug interactions when they are administered concomitantly with other drugs metabolised via the same pathway. In addition, protease inhibitors are substrates as well as inhibitors of the drug transporter P-glycoprotein, which also can result in pharmacokinetic drug interactions. The nucleoside reverse transcriptase inhibitors are predominantly excreted by the renal system and may also give rise to interactions. This review will discuss the pharmacokinetics of the different classes of antiretroviral drugs and the mechanisms by which drug interactions can occur. Furthermore, a literature overview of drug interactions is given, including the following items when available: coadministered agent and dosage, type of study that is performed to study the drug interaction, the subjects involved and, if specified, the type of subjects (healthy volunteers, HIV-infected individuals, sex), antiretroviral drug(s) and dosage, interaction mechanism, the effect and if possible the magnitude of interaction, comments, advice on what to do when the interaction occurs or how to avoid it, and references. This discussion of the different mechanisms of drug interactions, and the accompanying overview of data, will assist in providing optimal care to HIV-infected patients.

Drug Interaction of Fluvoxamine and Fluoxetine with Nevirapine in HIV-1-Infected Individuals.

OBJECTIVE: To evaluate the possible pharmacokinetic interactions between nevirapine and fluvoxamine or fluoxetine in patients with HIV-1 infection. PATIENTS AND METHODS: Patients who were using fluvoxamine or fluoxetine concomitantly were chosen from an unselected cohort (n = 173) of HIV-1-infected individuals using a nevirapine-containing regimen (study group). HIV-1-infected patients using nevirapine without fluvoxamine or fluoxetine and non-HIV-infected individuals who were using fluvoxamine and fluoxetine were included as controls. The influence of fluvoxamine and fluoxetine on the pharmacokinetics of nevirapine was investigated with a previously developed population pharmacokinetic model. Concomitant use of fluvoxamine or fluoxetine was tested independently as covariate for apparent clearance (CL/F) of nevirapine using nonlinear mixed-effect modelling (NONMEM). Furthermore, to explore the influence of nevirapine on the pharmacokinetics of fluvoxamine and fluoxetine, dose-normalised concentrations of fluvoxamine and fluoxetine from the study group were compared with those of the controls. RESULTS: Of the 173 HIV-1-infected individuals, 14 were using fluoxetine (n = 7) or fluvoxamine (n = 7) simultaneously with nevirapine. In addition, 17 and 29 individuals were identified as controls for the fluoxetine- and fluvoxamine-group, respectively. Concomitant use of fluvoxamine resulted in a significant reduction of 33.7% in CL/F of nevirapine; this reduction in CL/F appeared to be dose-dependent. Concomitant use of fluoxetine had no influence on the pharmacokinetics of nevirapine. Conversely, nevirapine significantly lowered plasma levels of fluoxetine plus norfluoxetine (seproxetine). In contrast, no significant difference was observed in dose-normalised concentrations of fluvoxamine when the controls were compared with the study group. CONCLUSION: We advise that special attention is paid to HIV-1-infected indivi-duals using a nevirapine-containing regimen and fluvoxamine or fluoxetine con-comitantly, since pharmacokinetic interactions have been observed.

Pharmacotherapy of Hospitalised HIV-Infected Patients in a General Hospital during 1990, 1997 and 2001.

OBJECTIVE: To describe the changes over time in drug therapy (antiretroviral as well as co-administered drugs) in HIV-infected patients who required hospitalisation during the period 1990-2001. In addition, we wanted to evaluate and compare the characteristics of these patients. DESIGN/SETTING: Retrospective review of hospitalisations of HIV-infected patients in a general hospital. RESULTS: During specified periods in 1990, 1997 and 2001, 22 patients out of 130 outpatients, 29 out of 394 outpatients, and 19 out of 570 outpatients, respectively, who were treated at the outpatient clinic were admitted 30, 38 and 27 times, respectively. The mean duration of these hospitalisations was 18.8, 14.2 and 16.7 days, respectively. The percentage of women and the mean age of the hospitalised patients increased over the studied time period. AIDS-related diagnoses decreased when comparing 1997 with 2001. The type of co-administered drugs of patients who required hospitalisation was fairly stable, but the total volume (defined as the mean volume of drugs per patient per bed-day) increased dramatically from 5.3 in 1990 to 6.8 in 1997 and to 15.5 in 2001. Dual and triple antiretroviral therapy decreased and became quadruple or greater therapy when 1997 and 2001 were compared. In addition, the number of hospitalised patients not treated with antiretroviral drugs increased from 1997 to 2001. CONCLUSION: The incidence of hospital admissions decreased but the volume of co-administered drugs increased from 1990 to 2001, suggesting extensive co-morbidity in the patients who still require hospitalisation.

Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals.

AIMS: To study the population pharmacokinetics of nevirapine and to identify relationships between patient characteristics and pharmacokinetics in an unselected population of patients attending our outpatient clinic. METHODS: Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital who were being treated with a nevirapine-containing regimen were included. During each visit, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters. Variables that were collected at baseline were serology for hepatitis B (HBV) and C (HCV) viruses, liver enzymes, and total bilirubin (TBR). In addition, information about concomitant use of St John's wort and patient demographics were included. The pharmacokinetics of nevirapine were described by first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (apparent clearance (CL/F), volume of distribution (V/F), absorption rate constant (k a)) were estimated, as were interindividual, interoccasion, and residual variability in the pharmacokinetics. The influence of patient characteristics on the pharmacokinetics of nevirapine was determined. RESULTS: From 173 outpatients a total number of 757 nevirapine plasma concentrations at a single random time point and full pharmacokinetic curves for 13 patients were available resulting in a database of 1329 nevirapine plasma concentrations. Mean CL/F, V/F, and k a were 3.27 l h-1, 106 l, and 01.66 h-1, respectively. CL/F of nevirapine was correlated with weight, chronic HCV infection, and baseline aspartate aminotransferase (ASAT). Chronic HCV and baseline ASAT> 1.5 x upper limit of normal (ULN) decreased CL/F by 27.4% and 13.2%, respectively, whereas an increase in body weight of 10 kg increased CL/F by 0.14 l h-1. A trend towards a lower CL/F in patients of the Negroid race was observed. No significant covariates were found for V/F. CONCLUSIONS: The pharmacokinetics of nevirapine were adequately described by our population pharmacokinetic model. Weight, chronic HCV infection, and baseline ASAT were found to be significant covariates for CL/F of nevirapine. The model incorporating these significant covariates may be an important aid in further optimizing nevirapine-containing therapy.

Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals.

To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study population.

Discrepancies between medical and pharmacy records for patients on anti-HIV drugs.

OBJECTIVE: To compare and evaluate drug notations in outpatient medical records and in pharmacy records in a cohort of HIV-1-infected patients treated with antiretroviral drugs. METHODS: Data on 103 patients were obtained from January 1, 1998, through December 31, 1999, by medical chart review and collection of pharmacy records. Two analyses were performed. First, antiretroviral drugs and comedication in the pharmacy records were documented and compared with their appearance in the outpatient medical records. Second, a detailed comparison was performed at 5 time points during the study period for the antiretroviral drugs. Generic name, formulation, strength, and frequency of dosing as registered in the outpatient medical records were compared with those registered in the pharmacy records. RESULTS: Total drug dispensation was 1607 (366 and 1241 antiretroviral drugs and comedication, respectively). The first screening resulted in a total discrepancy of 55.1% (n = 885), of which 97.1% (n = 859) was attributed to the comedication and 2.9% (n = 26) to the antiretroviral drugs. The discrepancy for the antiretroviral drugs at the specific time points ranged from 5.1% to 12.6% when the generic name only was used, and from 7.1% to 17% when formulation, strength, and frequency of dosing were also taken into account. CONCLUSIONS: The observed discrepancy between outpatient medical records and pharmacy records mainly concerns the comedication. For the antiretroviral drugs fewer, but still substantial, discrepancies were observed. These results indicate that full exchange of information conceming drug use in this population between general practitioners and specialists (infectious disease) is lacking.