Update on the pharmacokinetic aspects of antiretroviral agents: implications in therapeutic drug monitoring

The observed inter-individual variation in antiretroviral pharmacokinetics (PK) that results in a wide range of drug exposures from fixed-dose regimens has led to increasing interest in the clinical use of therapeutic drug monitoring (TDM) to individualize dosing of antiretroviral therapy (ART). The focus of this review is to provide an overview of literature available to support therapeutic drug monitoring among the current classes of antiretrovirals, suggest patient populations that may benefit from TDM and bring forth some of the limitations that may exist for widespread use of TDM in a traditional clinical setting.     

Augmented renal clearance in the Intensive Care Unit: an illustrative case series

The substantial underlying disease burden, in combination with the therapeutic interventions provided, can result in significantly altered end-organ function in the critically ill. These changes can in turn affect key pharmacokinetic (PK) indices for many antibiotics, including drug clearance, promoting potentially subtherapeutic concentrations for lengthy periods of the dosing interval, therapeutic failure or the selection of resistant organisms. This paper presents three instructional cases from our tertiary-level Intensive Care Unit, where established antibiotic dosing regimens failed to achieve predefined PK targets for optimal bacterial killing. Using therapeutic drug monitoring (TDM), significant dose modification was subsequently undertaken. We propose augmented renal clearance as a possible mechanism underlying this phenomenon, particularly in young post-operative, burns or head-injured patients with normal serum creatinine concentrations. TDM, or at least a measured creatinine clearance, should be considered early in this setting to allow the optimisation of antibiotic exposure.     

Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients

Objective  This study was conducted to retrospectively compare the area under the curve (AUC) and the total clearance of busulfan (Bu) following oral and intravenous (IV) administrations and to determine which intravenous dose generated equivalent exposure to that of the oral form that has been marketed for decades. Methods  Patient pharmacokinetics were assessed at dose 9 during a conditioning regimen for stem-cell transplantation and included data from 277 patients for oral Bu (71 from fixed-dose studies and 206 from studies with dose adjustment allowed) and 120 patients for IV Bu (fixed dose). AUCs were compared between patients with fixed dose of oral Bu (n = 71, 1 mg/kg) and those of IV Bu (n = 120, 0.8 mg/kg). Total clearances were calculated for all 277 patients with oral Bu and compared to those with IV Bu, with the ratio of IV-to-oral clearance representing the absolute bioavailability of the oral form. Results  Oral and IV populations differed on disease-type distribution but presented comparable demography parameters. IV Bu dosing was mostly based on the ideal body weight index while actual body weight or adjusted ideal body weight indexes were mostly used for oral. When normalised to comparable indexes, bioequivalent AUCs were achieved between oral and IV populations. Oral Bu bioavailability was about 80% when calculated from the ratio of IV-to-oral total clearances. Conclusion  This retrospective study carried out on a large set of data showed that similar plasma exposures were achieved with 1.0 mg/kg oral Bu or 0.8 mg/kg IV Bu.     

Individualized Dosing of Therapeutic Monoclonal Antibodies—a Changing Treatment Paradigm?

The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment. However, while beneficial, TDM does not provide sufficient information to effectively adjust doses. The pharmacokinetics (PK) and pharmacodynamics (PD) of mAbs are complex, with numerous factors impacting on mAb PK and PD. The concept of dashboard-guided dosing based on Bayesian PK models allows physicians to combine TDM with factors influencing mAb PK to individualize therapy more effectively. One issue with TDM has been the slow turnaround of assay results, either necessitating an additional clinic visit for a sample or reacting to TDM results at a subsequent, rather than the current, dose. New point-of-care (POC) assays for mAbs are being developed that would potentially allow physicians to determine drug concentration quickly. However, work remains to understand how to determine what target exposure is needed for an individual patient, and whether the combination of POC assays and dashboards presents a safe approach with substantial outcome benefit over the current standard of care.     

Decreased meropenem levels in Intensive Care Unit patients with augmented renal clearance: benefit of therapeutic drug monitoring

One of the first-line drugs for empirical antibiotic therapy in patients with hospital-acquired infections is meropenem. An often neglected problem in sepsis is that patients with a normal serum creatinine concentration (SCr) might display augmented renal clearance (ARC). Here we describe two cases of sepsis with subtherapeutic exposures with standard meropenem dosing in whom therapy could be optimised by therapeutic drug monitoring (TDM). A 37-year-old man with acute lymphatic leukaemia and sepsis had a normal SCr at the beginning of his Intensive Care Unit (ICU) stay but showed decreased SCr of between 30μmol/L and 40μmol/L during his stay. He failed to achieve effective plasma concentrations with the meropenem standard dose of 3g/day. Estimated glomerular filtration rate revealed values between 120mL/min and 160mL/min. He required a high meropenem daily dosage of 12g that was far above the approved maximum dose. A 66-year-old patient undergoing surgery of a pulmonary aspergilloma presented SCr persistently <50μmol/L, indicating ARC between 120mL/min and 150mL/min. This patient required 8g of meropenem to achieve effective plasma concentrations. TDM may represent an invaluable approach to optimising drug exposure of β-lactam antibiotics in patients with ARC in the ICU. Further trials are clearly needed to become better informed about empirical dosing regimens usable in the ICU setting with regard to the relevance of ARC. In the meantime, daily measurement of creatinine clearance as well as TDM can be used to identify patients who manifest ARC, thereby allowing drug therapy to achieve the therapeutic range.     

Neonatal therapeutic drug monitoring--its clinical relevance

The potential clinical usefulness of therapeutic drug monitoring (TDM) in neonates is discussed. The personnel performing neonatal TDM must be knowledgeable in the many clinical, analytical, and pharmacokinetic variables used for measuring drug concentrations to formulate rational, individualized dosing regimens. Examples of variables and their effects on TDM interpretations are given and some gaps in our knowledge are presented. The theoretical promise of neonatal TDM is contrasted with the practical realities.     

Practical Considerations for Dose Selection in Pediatric Patients to Ensure Target Exposure Requirements

Pediatric dosing recommendations are often not based on allometry, despite recognition that metabolic processes in mammals scale to the ¾ power. This report reviews the allometric size model for clearance and its implications for defining doses for children while considering practical limitations. Fondaparinux exposures in children were predicted using allometric and mg/kg dosing. Additional simulations further refined the dose based on the predicted Cmax, target exposure range, complexity of the dosing regimen, and previous exposure/response data. The percent reduction of the adult dose of an oral lozenge fixed-dose formulation which would predict similar exposures in children and adults was recommended based on simulations. Allometric dosing predicted a consistent fondaparinux exposure across the weight range. Size-optimized mg/kg dosing, which partially approximates the allometric relationship, allows for consistent fondaparinux exposures (i.e., 0.12 mg/kg ≤35 kg or 0.1 mg/kg >35 kg). Simulations of the oral lozenge formulation demonstrated rapidly changing clearance in children less than 6 years prohibiting practical dosing recommendations for satisfying all conventional exposure metrics (Cmax and AUC) in this age group. In children between 13 and 18 or 6 and 13 years, a 8.6% and 54% reduction in dose would maintain target exposures but dose reductions of 12.5% or 62.5% were ultimately recommended as deemed manufacturable. Dose selection in children should consider the known and/or predicted covariate relationships which affect exposure. Presented examples applied the allometric model in dose selection with the goal of PK bridging and considered practical limitations in dose selection.     

Machine Learning for Pharmacokinetic/Pharmacodynamic Modeling

A variety of new recurrent neural networks (RNNs) including the ODE-LSTM, Phased LSTM, CTGRU and GRU-D, were evaluated on modeling irregularly sampled PK/PD data with 6 or 12 time points/day and predicting PD data of unseen dosing regimens and dosing levels. The one-compartment absorption PK model and the Indirect PK/PD model I was used to simulate the PK/PD with inter-individual variabilities in volume of distribution and residual errors in PD measurement. The four RNNs were able to successfully model daily dose (QD) PK/PD and extrapolate to twice daily (BID) dose PD based on BID PK. The RNNs not only captured the additional fluctuations in the BID regimen but also the return phase to the baseline PD. However, extrapolating to unseen dose levels outside of the dose range for training proved to be challenging for all the RNNs tested. Only the GRUD demonstrated reasonable prediction results when extrapolating to unseen doses that were 3 or 10-fold outside the training doses. Overall, these new RNNs were able to overcome some limitations of previous RNNs evaluated and showed promise of integrating neural networks in PK/PD.     

Population Pharmacokinetic Modeling of Subcutaneously Administered Etanercept in Patients with Psoriasis

The objective of this paper is to present a population PK model which adequately describes the time–concentration profiles of different doses of etanercept (Enbrel^®) administered subcutaneously to subjects with moderate-to-severe psoriasis and to simulate the time courses of concentrations following 50 mg once weekly (QW) dosing. Pharmacokinetic (PK) data from three clinical studies with doses 25 mg QW, 25 mg twice weekly (BIW) and 50 mg BIW, were used. A one-compartment model with gender, weight and time covariates on the apparent clearance and weight covariate on the apparent volume of distribution was developed. The population mean of the apparent steady state clearance in males was 0.129 l/h, compared to 0.148 l/h in females. The clearance varied with time being lower in the first 2 weeks of the therapy, increasing sharply during weeks 3–4, and converging gradually after that to its steady state level. The population mean of the apparent volume of distribution also varied with time and was 16.1 l during week 1, 20.0 l during weeks 2–4 and 22.5 l after week 4. The population PK model adequately described the observed concentration–time profiles in subjects with psoriasis. Despite a somewhat different covariate set, the parameter estimates of the population PK model for etanercept are very similar between the psoriasis and rheumatoid arthritis populations. The population PK model was used to simulate the pharmacokinetic profiles after a novel 50 mg QW dosing regimen. The simulations show good agreement with the observed data from 84 subjects participating in a fourth study (50 mg QW dose) used as an external validation set. The simulations of the 50 mg QW and the 25 mg BIW dosing regimens show that there is a significant overlap between the profiles yielding similar steady state exposures with both dosing regimens. The latter is an indication that the respective efficacy and safety profiles after those two dosing regimens are likely to be similar.     

Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients < or = 12 kg should be dosed at 1.1 mg/kg and those > 12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.     

Pharmacoeconomic Impact of Once-Daily Aminoglycoside Administration

A retrospective cost analysis compared hospital costs of standard gentamicin dosing and once-daily regimens in 1127 patients. Hospital costs compared were drug/supply/preparation/administration (DSPA; $4.56/500 mg once-daily dose and $3.32/100 mg every 8 hrs standard dose); therapeutic drug monitoring (TDM) ($25/gentamicin level); and nephrotoxicity management. The mean length of therapy was 4.5 days with both regimens. The mean number of blood samples drawn to measure drug levels was 0.65 for once-daily dosing and 1.7 for standard dosing. Mean DSPA and TDM costs/patient for a 4.5-day course of once-daily therapy were $20.52 and $16.25, respectively ($36.77/course of therapy). In comparison, estimated mean DSPA and TDM costs for 4.5 days standard therapy were $44.82 and $42.50, respectively ($87.32/course of therapy). We observed an overall reduction in nephrotoxicity from approximately 4% to 1.2% with the once-daily program, resulting in a nephrotoxicity management cost reduction from $182 to $55/patient exposed to aminoglycosides. The once-daily program resulted in a 58% reduction in aminoglycoside-associated hospital cost and a nephrotoxicity management savings of 70%/patient.     

Therapeutic drug monitoring in pregnancy

ABSTRACT:: Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.     

Remedial dosing recommendations for valproic acid in nonadherence patients with epilepsy

OBJECTIVE To investigate the effect of delayed or missed doses on the pharmacokinetics(PK)of valproic acid(VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherence patients. METHODS The Monte Carlo simulations based on all previous population pharmacokinetic models for pediatric, adult and elder patients with epilepsy receiving valproic acid. The following three remedial approaches were investigated for each delayed dose:(1) A partial dose was administered immediately, and the regular dose was administered at the next scheduled time.(2)The delayed dose was administered immediately, fol owed by a partial dose at the next scheduled time.(3)The delayed and partial doses were coadministered immediately, the next scheduled dose was skipped, and the regular dosing was resumed at the subsequent scheduled time. RESULTS The most appropriate remedial regimen was that with the shortest deviation time from the therapeutic window. The effect of nonadherence on PK was dependent on the delay duration and daily dose, and the recommended remedial dose was related to the delay duration and concomitant antiepileptic drugs. Remedial dosing strategies(1) and(2) were almost equivalent, whereas(3)showed a larger PK deviation time. If one dose was missed, double doses were not recommended for the next scheduled time. CONCLUTION Simulations provide quantitative insight into the remedial regimens for nonadherence patients and clinicians should select the optimal regimen based on the status of patients.     

Innovative approaches to optimizing the delivery of vancomycin in individual patients

The delivery of personalized antimicrobial therapy is a critical component in the treatment of patients with invasive infections. Vancomycin, the drug of choice for infections due to methicillin-resistant Staphylococcus aureus, requires the use of therapeutic drug monitoring (TDM) for delivery of optimal therapy. Current guidance on vancomycin TDM includes the measurement of a trough concentration as a surrogate for achieving an AUC to minimum inhibitory concentration (MIC) by broth microdilution (AUC/MIC_BMD) ratio ≥ 400. Although trough-only monitoring has been widely integrated into clinical practice, there is a high degree of inter-individual variability between a measured trough concentration and the actual AUC value. The therapeutic discordance between AUC and trough may lead to suboptimal outcomes among patients with infections due to less susceptible pathogens or unnecessarily increase the probability of acute kidney injury (AKI) in others. Given the potentially narrow vancomycin AUC range for optimal effect and minimal AKI, clinicians need a “real-time” system to predict accurately the AUC with limited pharmacokinetic (PK) sampling. This article reviews two innovative approaches for calculating the vancomycin AUC in clinical practice based on one or two drug concentrations. One such approach involves the use of Bayesian computer software programs to estimate the “true” vancomycin AUC value with minimal PK sampling and provide AUC-guided dosing recommendations at the bedside. An alternative involves use of two concentrations (peak and trough) and simple analytic equations to estimate AUC values. Both approaches provide considerable improvements over the current trough-only concentration monitoring method.     

Pitfalls in TDM of antibiotic drugs: analytical and modelling issues

The quality assurance program of the Dutch KKGT [Association for Quality Assessment in therapeutic drug monitoring (TDM) and Clinical Toxicology] has been running for more than 25 years. One of these programs concerns TDM of the antibiotic drugs gentamicin, tobramycin, amikacin, and vancomycin. We present two issues encountered in a recent survey. In a case of gentamicin monitoring and dose-adjustment, a systematic analytical error in some centers led to a dosing recommendation that differed from that of the organizers. Correction of the analytical results on the basis of a standard control sample resulted in concentration differences of more than 20% and different dosing recommendations in these centers. In a case of vancomycin TDM, the choice of the population model proved to be critical for dose adjustment. We illustrate this example by presenting the plasma profiles derived from the different population models used by the participants.     

How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics

Optimising antimicrobial dosing for critically ill patients is highly challenging and when it is not achieved can lead to worse patient outcomes. To this end, use of dosing regimens recommended in package inserts from drug manufacturers is frequently insufficient to guide dosing in these patients appropriately. Whilst the effect of critical illness pathophysiology on the pharmacokinetic (PK) behaviour of antimicrobials can be profound, the variability of these changes between patients is still being quantified. The PK effects of hypoproteinaemia, organ dysfunction and the presence of augmented renal clearance may lead to plasma antimicrobial concentrations that are difficult to predict at the bedside, which may result in excess toxicity or suboptimal bacterial killing. This paper outlines the factors that affect pharmacokinetics in critically ill patients and how knowledge of these factors can increase the likelihood of achieving optimal antimicrobial plasma concentrations. In selected settings, we advocate individualised dosing of renally cleared antimicrobials using physiological data such as measured creatinine clearance and published non-renal clearance data. Where such data do not exist, therapeutic drug monitoring may be a useful alternative and has been associated with significant clinical benefits, although it is not currently widely available.     

A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.     

Predicting the usefulness of therapeutic drug monitoring of mycophenolic acid: a computer simulation

The usefulness of therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) was investigated with a computer simulation model. For a fixed-dose (FD) and a concentration-controlled (CC) MMF dosing regimen exposure to mycophenolic acid (MPA) was compared. A nonlinear mixed-effects model (NONMEM) for MPA based on extensive pharmacokinetic data from 140 renal transplant recipients who all used cyclosporine and corticosteroids as maintenance immunosuppressive therapy provided Bayesian estimates for MPA oral clearance on 9 occasions during the first 24 weeks after transplantation. In 45 of these patients, the estimates for MPA oral clearance were used to calculate values for the area under the curve (AUC) of MPA. In the CC group, MMF doses were adjusted based on the calculated AUC, targeting at an AUC level of 45 mg.h/L. In the FD group, MMF doses were fixed at 1000 mg. On day 7 after transplantation, significantly more AUC values were on target (AUC range 30-60 mg.h/L) in the CC group than in the FD group: 76% versus 13%, respectively, P < 0.001. To accomplish this, a doubling of MMF dose was necessary in more than half of the patients after the AUC assessment on day 3 after transplantation. Between-patient variability (BPV) in AUC (average CV% for all occasions) was reduced in the CC regimen: 23% versus 44% in the FD group. By using TDM, adequate MPA exposure appears to be obtained more rapidly, and BPV in exposure is reduced. To reach target AUC levels as soon as possible in this cyclosporine-treated population, it appears that larger MMF doses as currently recommended are necessary in the first month after transplantation.     

Vancomycin dosing and therapeutic drug monitoring practices: guidelines versus real-life

Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1–Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved.