Guidance Of Therapeutic Drug Monitoring Research Articles

Dose adjustment strategy of levetiracetam in pregnant patients with epilepsy: Case report and literature review.

Pregnant patients with epilepsy are prone to preterm delivery, stillbirth, or cesarean section, and their mortality rate is almost 10 times higher than that of normal pregnant women. The potential negative influences of antiepileptic drugs (AEDs) on the fetus are weighed against the necessity for achieving optimal control of seizures. Treatment with AEDs during pregnancy is a major challenge for pregnant women and healthcare teams. This paper reports two cases of young women diagnosed with pregnancy and epilepsy. The dose of levetiracetam was adjusted under the guidance of therapeutic drug monitoring to reduce the effects of seizures on the fetus and the incidence of reproductive toxicity caused by adverse drug reactions. Epilepsy was well controlled in the two pregnant patients, and the newborns had no genetic disorders. It is recommended to regularly monitor the serum LEV level in pregnant patients with epilepsy. This practice serves as a foundation for adjusting the drug treatment plan and offering more precise guidance for medication management during pregnancy.

Which Are the Best Regimens of Broad-Spectrum Beta-Lactam Antibiotics in Burn Patients? A Systematic Review of Evidence from Pharmacology Studies.

Burn injury causes profound pathophysiological changes in the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics. Infections are among the principal complications after burn injuries, and broad-spectrum beta-lactams are the cornerstone of treatment. The aim of this study was to review the evidence for the best regimens of these antibiotics in the burn patient population. We performed a systematic review of evidence available on MEDLINE (from its inception to 2023) of pharmacology studies that focused on the use of 13 broad-spectrum beta-lactams in burn patients. We extracted and synthetized data on drug regimens and their ability to attain adequate PK/PD targets. We selected 35 studies for analysis. Overall, studies showed that both high doses and the continuous infusion (CI) of broad-spectrum beta-lactams were needed to achieve internationally-recognized PK/PD targets, ideally with therapeutic drug monitoring guidance. The most extensive evidence concerned meropenem, but similar conclusions could be drawn about piperacillin-tazobactam, ceftazidime, cefepime, imipenem-clinastatin and aztreonam. Insufficient data were available about new beta-lactam-beta-lactamase inhibitor combinations, ceftaroline, ceftobiprole and cefiderocol. Both high doses and CI of broad-spectrum beta-lactams are needed when treating burn patients due to the peculiar changes in the PK/PD of antibiotics in this population. Further studies are needed, particularly about newer antibiotics.

A simple and rapid HPLC-MS/MS method for therapeutic drug monitoring of amikacin in dried matrix spots

Individualized treatment of amikacin under the guidance of therapeutic drug monitoring (TDM) is important to reduce the occurrence of toxicity and improve clinical efficacy. In the present study, we developed and validated a simple and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of amikacin in dried matrix spots (DMS) which the matrix is serum. DMS samples were obtained by spotting volumetric blood onto Whatman 903® cards. Samples were punched into 3 mm diameter discs and extracted with 0.2 % formic acid in water. The HILIC column (2.1 mm × 100 mm, 3.0 µm) under gradient elution was applied, and the analysis time was 3 min per injection. The mass spectrometry transitions were m/z 586.3 → 163.0 for amikacin and m/z 591.4 → 163.1 for D5-amikacin. Full validation was conducted for DMS method, and the method was applied for the amikacin TDM and compared with serum method. The linearity was ranged from 0.5 to 100 mg/L. Both within-run and between-run accuracy and precision of DMS ranged from 91.8 % to 109.6 % and 3.6 % to 14.2 %, respectively. The matrix effect was 100.5 %–106.5 % of DMS method. Amikacin remained stable in DMS for at least 6 days at room temperature, 16 days at 4 °C, 86 days at −20 °C and −70 °C. A good agreement between the DMS method and serum method has been shown in Bland-Altman plots and Passing-Bablok regression. All of the results demonstrated that the DMS methods can be a favorable replacement for amikacin TDM.

Effectiveness and Safety of Beta-Lactam Antibiotics with and without Therapeutic Drug Monitoring in Patients with Pseudomonas aeruginosa Pneumonia or Bloodstream Infection.

This objective of this study was to compare clinical outcomes in hospitalized patients with Pseudomonas aeruginosa pneumonia (PNA) or bloodstream infection (BSI) receiving beta-lactam antibiotic (BLA) infusions with and without the guidance of therapeutic drug monitoring (TDM). A retrospective, parallel cohort study was conducted at two academic medical centers between December 2015 and January 2020, UF Shands Gainesville, which uses BLA TDM for select patients (BLA TDM), and UF Health Jacksonville, which does not use BLA TDM (No-BLA TDM). All hospitalized adult patients with respiratory or blood culture positive for P. aeruginosa who met diagnosis criteria for lower respiratory tract infection with a positive P. aeruginosa respiratory culture and who received ≥48 h of intravenous BLA with in vitro susceptibility within 72 h of positive culture collection were included. The primary outcome was a composite of presumed treatment failure defined as the presence of any of the following from index-positive P. aeruginosa culture collection to the end of BLA therapy: all-cause mortality, escalation of and/or additional antimicrobial therapy for P. aeruginosa infection after 48 h of treatment with susceptible BLA due to worsening clinical status, or transfer to a higher level of care (i.e., the intensive care unit [ICU]). Analyses were adjusted for possible confounding with inverse probability of treatment weighting (IPTW). Two-hundred patients were included (BLA TDM, n = 95; No-BLA TDM, n = 105). In IPTW-adjusted analysis of the primary composite endpoint, BLA TDM demonstrated a significant decrease in presumed treatment failure compared to No-BLA TDM (adjusted odds ratio [aOR] 0.037, 95% confidence interval [CI] [0.013 to 0.107]; P < 0.001). BLA TDM had more 30-, 60- and 90-day infection-related readmissions ([aOR], 11.301, 95% CI (3.595 to 35.516); aOR 10.389, 95% CI [2.496 to 43.239], and aOR 24.970, 95% CI [6.703 to 93.028]) in IPTW analyses. For both unadjusted and IPTW-adjusted cohorts, there was no significant difference in hospital and ICU length of stay, adverse effects while on BLA, or microbiological eradication between BLA TDM and No-BLA TDM. In hospitalized adult patients with P. aeruginosa PNA or BSI, the use of TDM-guided BLA infusions decreased the odds of presumed treatment failure compared to patients receiving BLA infusions without TDM guidance. Future studies should evaluate BLA TDM impact on readmission.

Approaching 65 Years: Is It Time to Consider Retirement of Vancomycin for Treating Methicillin-Resistant Staphylococcus aureus Endovascular Infections?

Vancomycin was introduced nearly 65 years ago and remains the standard antibiotic for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Staphylococcus aureus remains highly susceptibility to vancomycin (>97%). Despite this, MRSA treatment failure with vancomycin is high in complicated bacteremia. Additionally, vancomycin can cause nephrotoxicity, leading to new therapeutic drug monitoring guidance. This demonstrates how difficult it is to dose vancomycin in a way that is both efficacious and safe, especially during long courses of therapy. Often underappreciated are the cost, resources, and complexity of vancomycin care at a time when alternative antibiotics are becoming cost comparable. This perspective highlights a bigger picture of how the treatment repertoires of many other diseases have changed and advanced since vancomycin’s introduction in the 1950s, yet the vancomycin MRSA treatment standard remains. While vancomycin can still have a role, 65 years may be a practical retirement age for vancomycin in highly complex endovascular infections.

1114. Effectiveness and Safety of Beta-lactam Antibiotics with and without Therapeutic Drug Monitoring in Patients with Pseudomonas aeruginosa Pneumonia or Bloodstream Infection

Background Pseudomonas aeruginosa (PSAR) is challenging to treat due to its multiple resistance mechanisms, limited anti-PSAR agents, and population pharmacokinetic (PK) variances. Beta-lactam antibiotics (BLA) are commonly used to treat PSAR infections and although they have a wide therapeutic index, suboptimal exposures may lead to treatment failure and antimicrobial resistance while high exposure may result in adverse effects. Certain patient populations may benefit from BLA therapeutic drug monitoring (TDM) due to their significant PK variability. The purpose of this study was to compare clinical outcomes in patients with PSAR pneumonia (PNA) or bloodstream infection (BSI) receiving BLA with and without the guidance of TDM.MethodsRetrospective, parallel cohort study conducted at UF Shands Gainesville and UF Health Jacksonville evaluating five years of patients with PSAR PNA or BSI. TDM group was defined for routine BLA TDM compared to nonroutine BLA TDM service (non-TDM). Patients were excluded if they died before a culture result, transferred in with a positive PSAR culture, were transplant recipients, cystic fibrosis or burn injury patients. The primary outcome was a composite of presumed clinical cure defined as the absence of the following: all-cause in-hospital mortality, escalation, and/or additional antimicrobial therapy for PSAR infection after 48 hours of treatment with primary susceptible regimen due to worsening clinical status or transfer to a higher level of care.ResultsTwo-hundred patients were included (TDM n=95; non-TDM n=105). The overall primary composite outcome of presumed clinical cure occurred in 73% of patients (82% and 75% of the TDM and non-TDM cohorts, respectively; p=0.301). A post-hoc multivariate analysis was conducted to assess predictors of not attaining clinical cure. ConclusionWhile there was no difference in the primary composite outcome of presumed clinical cure, future studies can use these data to assess TDM patient selection and whether a bundled care approach of BLA regimens with known clinical benefit, early TDM-guided dose optimization, and continued clinical assessment improves outcomes in patients with PSAR PNA or BSI compared to use of each modality individually. Disclosures All Authors: No reported disclosures

Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease.

BackgroundInfliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics.MethodsThe study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed‐effects population pharmacokinetic modeling.ResultsDose‐normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10–21) compared to prepregnancy (7, 2–12; p = 0.003), the first trimester (9, 1–12; p = 0.04), or postpregnancy (6, interquartile range 3–11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7–36; p > 0.05). A one‐compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti‐infliximab antibodies, and not by pregnancy‐imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre‐ and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester.ConclusionInfliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de‐intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.

Effects of antifungal drugs on the plasma concentrations and dosage of tacrolimus in kidney transplant patients

ObjectivesTacrolimus is one of the three basic immunosuppressants used following kidney transplantation, and its plasma concentration is susceptible to antifungal drugs. Abnormal tacrolimus concentrations may lead to adverse outcomes for...

Implications of Evolving and Emerging Pharmacokinetic-Pharmacodynamic Research for Triazoles and Echinocandins

Clinicians should be encouraged to use pharmacokinetic-pharmacodynamic (PK-PD) studies to optimize antifungal drug dosing in the absence of robust comparative effectiveness data or in cases where evidence of causality has not yet been firmly established. The purpose of this article is to review how new triazole and echinocandin PK-PD studies have contributed to our current understanding of antifungal selection and dose optimization against invasive fungal infections. Emerging infections such as C. auris and novel antifungal drugs such as rezafungin will also be highlighted. Future research endeavors are suggested where currently robust clinical outcomes data associated with PK-PD target attainment are lacking. Recent results from clinical fluconazole PK-PD studies may indicate that unique AUC24/MIC thresholds exist for specific Candida species. The inability of recent studies to confirm previous fluconazole AUC24/MIC clinical PK-PD targets of 11 to 400 may also be due to previously unrecognized PK variability in special patient populations such as those with augmented renal clearance. A free AUC24/MIC threshold of 25 appears to be conserved across the azole antifungal class in animal models of invasive candidiasis. Current therapeutic drug monitoring guidance with voriconazole, posaconazole, and itraconazole has been used to indirectly confirm pre-clinical AUC24/MIC PK-PD targets in invasive candidiasis and aspergillosis. Elucidation of the PK-PD targets in pre-clinical models has led to successful isavuconazole dose optimization in human studies and has contributed to dosing recommendations for the novel echinocandin rezafungin. PK-PD research will also be important in guiding antifungal selection against infections caused by emerging pathogens, such as Candida auris, and those caused by fungi for which reduced susceptibility is a growing concern, including Coccidioides species and azole-resistant Aspergillus fumigatus. PK-PD research may be used to inform treatment decisions for rare fungal infections, infections with rapidly changing epidemiology, in patient populations expected to have altered pharmacokinetics, for novel antifungal drugs or those with new formulations, and in cases where evidence of causality cannot be established from large randomized comparative studies. A number of animal models have been developed and more clinical PK-PD studies are being conducted. In the absence of clinical PK-PD outcome data in human studies, researchers have expanded the use of currently available therapeutic drug monitoring to gain insight into possible PK-PD targets.

Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam to improve outcome in patients with sepsis (TARGET): a prospective, multi-centre, randomised controlled trial

BackgroundSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection with a hospital mortality in excess of 40%. Along with insufficient and delayed empirical antimicrobial therapy, inappropriate antimicrobial exposure has been identified to negatively affect patient outcomes. Receipt of prolonged infusion (i.e. extended or continuous infusion) of piperacillin/tazobactam (TZP) improves antimicrobial exposure and is associated with reduced mortality in patients with sepsis. Using therapeutic drug monitoring (TDM) with dosing tailored to the altered pharmacokinetics of the individual patient to avoid under- and overdosing may be a further strategy to improve patient outcomes. This current trial will address the question whether a TDM-guided therapy with TZP administered by continuous infusion will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion of the total daily dose of TZP without TDM.MethodsThe study is an investigator-initiated, multi-centre, parallel-group, single-blinded, randomised controlled trial. The trial will be conducted in several centres across Germany. Adult patients (aged ≥ 18 years) with severe sepsis or septic shock will be eligible for study participation. Participants will be randomly assigned to receive either TZP by continuous infusion guided by daily TDM of piperacillin (experimental group) or by continuous infusion without TDM guidance (total daily dose in normal renal function 13.5 g TZP) (control group). The pharmacokinetic (PK)/pharmacodynamic (PD) target will be 100% f T>4MIC (percentage of time during a dosing interval that the free [f] drug concentration exceeds 4 times the minimum inhibitory concentration). The primary efficacy endpoint is the change in mean total Sequential Organ Failure Assessment score from day 1 after randomisation until day 10 or discharge from the intensive care unit or death, whichever comes first. Secondary outcomes include mortality, clinical cure, microbiological cure, overall antibiotic use, individual components of the primary outcome, adverse events and analysis of PK and (PD) indices.DiscussionThis trial will assess for the first time whether continuous infusion of TZP guided by daily TDM in patients with sepsis will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion without TDM.Trial registrationGerman Clinical Trials Register (GermanCTR), DRKS00011159. Registered on 10 October 2016.

Research of optimal dosing regimens and therapeutic drug monitoring for vancomycin by clinical pharmacists: analysis of 7-year data

To investigate the effectiveness and safety of clinical pharmacists-directed vancomycin dosing and therapeutic drug monitoring (TDM), and to promote the individualized medication of vancomycin. Information of hospitalized patients treated by vancomycin admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2011 to October 2017 was collected retrospectively during study period, the patients were divided into pharmacists intervention and non-pharmacists intervention groups according to pharmacist-directed vancomycin dosing guideline or not. The individualized dosing regimen of vancomycin for the patients in pharmacists intervention group was guided by clinical pharmacists, this guideline was that pharmacists offered the TDM guidance, made the individualized dosage regimen of vancomycin, etc., which based on the patients' pathophysiology, condition, and the adjustments of increased dose or 24-hour continuous infusion vancomycin were made for patients if the steady-state trough concentrations fell below the target level. Vancomycin dosage was made for patients in the non-pharmacists intervention group by physicians only based on vancomycin instructions or clinical experience. The vancomycin dosing, TDM, microorganism culture, renal function, 30-day mortality rate, and length of hospital stay were recorded. The appropriateness of TDM for vancomycin was defined as a blood collection within 1 hour of the next scheduled dose after steady state achieved. The rationality of the initial dosing regimen was determined based on the vancomycin application guidelines issued by Infectious Diseases Society of America (IDSA) in 2009. A total of 258 patients were enrolled, and there were 158 patients in the non-pharmacists intervention group and 100 in pharmacists intervention group. The appropriateness of TDM for vancomycin in pharmacists intervention group was significantly improved as compared with that in non-pharmacists intervention group [87.0% (87/100) vs. 69.6% (110/158), P < 0.01], the percentage of first trough serum concentrations drawn on day 3 after steady state achieved was significantly increased [51.0% (51/100) vs. 37.3% (53/142), P < 0.05]. Compared with the non-pharmacists intervention group, the percentages of patients who received appropriate initial dosing and attained the initial target therapeutic range in pharmacists intervention group were significantly increased [87.4% (76/87) vs. 68.2% (75/110), 51.7% (45/87) vs. 30.9% (34/110), both P < 0.01], the percentage of patients whose vancomycin dosing regimen was adjusted based on TDM results was also significantly increased [54.0% (47/87) vs. 15.5% (17/110), P < 0.01], the rate of vancomycin serum concentrations reaching the standard was increased [70.1% (61/87) vs. 32.7% (36/110), P < 0.01], and a lower number of patients in sub- or supra-therapeutic range was observed in pharmacists intervention group [27.6% (24/87) vs. 46.4% (51/110), 2.3% (2/87) vs. 20.9% (23/110), both P < 0.01]. In addition, a lower incidence of vancomycin-induced acute kidney injury (AKI) was observed in pharmacists intervention group as compared with that in non-pharmacists intervention group [0 (0/87) vs. 6.4% (7/110), P < 0.01]. No significant difference was observed in the microorganism culture, 30-day mortality rate or length of hospital stay between the two groups. Among the 87 patients in pharmacists intervention group, the vancomycin dosing was adjusted for 42 patients who did not attain the target therapeutic range, increasing the dose of vancomycin was made for 22 patients, 24-hour continuous infusion was made for 20 patients. Compared with the only increasing vancomycin dose group, vancomycin continuous infusion for 24 hours could significantly increase the serum trough concentration (mg/L: 18.0±6.7 vs. 12.5±5.8, P < 0.05), and reduce daily dosage (mg/kg: 27.1±7.1 vs. 36.6±9.2, P < 0.01). The implementation of a pharmacist-directed vancomycin dosing guideline based on TDM optimized vancomycin dosing regimen, improved the accuracy and timeliness of TDM for vancomycin, achieved a higher percentage of levels within the therapeutic range, and a lower incidence of vancomycin-induced AKI.

Effectiveness of half-a-tablet efavirenz plus 2 nucleos(t)ide reverse-transcriptase inhibitors as maintenance therapy with the guidance of therapeutic drug monitoring among virologically suppressed HIV-positive patients: A prospective study.

Optimal efavirenz (EFV) dose that minimizes adverse effects while maintaining efficacy has yet to be elucidated. With a therapeutic drug monitoring (TDM)-guided strategy, we assessed the effectiveness of half-a-tablet EFV plus 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) in HIV-infected Taiwanese who had achieved viral suppression with full-dose (600mg) EFV. HIV-infected adults receiving EFV-containing regimens who had plasma mid-dose EFV concentration (C12) ≥2.0mg/L and had plasma HIV RNA load (PVL)<200 copies/mL were enrolled in this single-arm, open-label study by reducing EFV to half-a-tablet daily. The primary endpoint was PVL <50 copies/ml in an intention-to-treat (ITT) population at week 48. The secondary endpoints were the plasma EFV C12, the proportion of patients with plasma EFV C12<1.0mg/L, PVL <50 copies/ml at week 96 and week 144. Between April 2013 and September 2016, 203 patients (93.6% male; median age, 39.0 years) were enrolled. The median EFV C12 before switch was 2.80mg/L (interquartile range (IQR), 2.41-3.73), which decreased to 1.59mg/L (IQR, 1.23-2.03) after switch with a reduction of 47.4% (IQR, 38.3-55.5%). In ITT analysis, 93.6%, 92.3% and 87.3% of the patients achieved PVL <50 copies/ml at weeks 48, 96 and 144, respectively. More than 70% of the patients reported alleviation of EFV-associated adverse effects following the switch. Under the guidance of TDM, switch to half-a-tablet EFV plus 2 NRTIs is effective in maintaining viral suppression in HIV-infected Taiwanese with EFV C12≥2.0mg/L.

Treatment response to unboosted atazanavir in combination with tenofovir disoproxil fumarate and lamivudine in human immunodeficiency virus-1-infected patients who have achieved virological suppression: A therapeutic drug monitoring and pharmacogenetic study

Treatment response to switch regimens containing unboosted atazanavir and tenofovir disoproxil fumarate (TDF)/lamivudine guided by therapeutic drug monitoring in human immunodeficiency virus-infected patients is rarely investigated. Consecutive patients with plasma human immunodeficiency virus RNA load<200copies/mL switching to unboosted atazanavir plus zidovudine-lamivudine (coformulated), abacavir-lamivudine (coformulated), or TDF/lamivudine>3months were included for determinations of treatment response, plasma atazanavir concentrations, and single-nucleotide polymorphisms of MDR1, PXR, and UGT1A1 genes from 2010 to 2014. Treatment failure was defined as either discontinuation of atazanavir for any reason or plasma viral load ≥200copies/mL within 96weeks. During the study period, 128 patients switched to unboosted atazanavir with TDF/lamivudine (TDF group) and 186 patients switched to unboosted atazanavir with two other nucleoside reverse-transcriptase inhibitors (non-TDF group). There were no statistically significant differences in the distributions of single-nucleotide polymorphisms of MDR1 (2677 and 3435), PXR genotypes (63396), and UGT1A1*28 between the two groups. Recommended plasma atazanavir concentrations were achieved in 83.5% and 64.9% of the TDF group and non-TDF group, respectively (p<0.01). After a median follow-up duration of 96.0weeks, treatment failure occurred in 19 (14.9%) and 34 (18.3%) patients in the TDF group and non-TDF group, respectively (p=0.60). Low-level viremia (40-200 copies/mL) before switch (adjusted hazard ratio, 2.12; 95% confidence interval, 1.12-4.01) and without therapeutic drug monitoring (adjusted hazard ratio, 2.08; 95% confidence interval, 1.16-3.73) were risk factors for treatment failure. Switch to unboosted atazanavir with TDF/lamivudine achieves a similar treatment response to that with two other nucleoside reverse-transcriptase inhibitors in patients achieving virological suppression with the guidance of therapeutic drug monitoring.

Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring

Center for Infection Control, National Taiwan University Hospital, Taipei City, Taiwan. Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan. Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsin-Chu city, Taiwan. Clinical Laboratory Sciences and Medical Biotechno, National Taiwan University College of Medicine, Taipei City, Taiwan. Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei City, Taiwan.

Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring.

IntroductionWide inter-patient variation of plasma efavirenz (EFV) concentrations has been observed, and a substantial proportion of HIV-positive patients may have unnecessarily higher plasma EFV concentrations than recommended while receiving EFV-containing combination antiretroviral therapy (cART) at the currently recommended daily dose of 600 mg. A lower daily dose (400 mg) of EFV has recently been demonstrated to be as efficacious as the recommended 600 mg when combined with tenofovir/mtricitabine in a multinational clinical trial, with a lower incidence of adverse effects. We aimed to use a therapeutic drug monitoring (TDM)-guided strategy to optimize the EFV dose in HIV-positive Taiwanese patients.Materials and MethodsThe plasma EFV concentrations at 12 hours (C12) after taking the previous dose were determined among HIV-positive adults who had received EFV-containing cART with viral suppression (plasma HIV RNA load (PVL) <200 copies/mL). For those with EFV C12 >2.0 mg/L, EFV (Stocrit, MSD) was reduced to half a tablet daily. Determinations of EFV C12 were repeated 4–12 weeks after switch using high-performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase-chain-reaction restriction fragment-length polymorphism.ResultsBetween April 2013 and June 2014, 111 patients (95.5% male; mean age, 39 years; 96.4% with PVL <40 copies/ml; 26.4% HBsAg-positive and 7.5% anti-HCV-positive) with plasma C12 efavirenz >2.0 mg/L were switched to a reduced dose (1/2# hs) of EFV; 45.5% of them had CYP2B6 G516T or TT genotypes; and 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/L (interquartile range (IQR), 2.62–4.17) for 111 patients, which decreased to 1.96 mg/L (IQR, 1.53–2.33) for 64 patients who had completed follow-up of C12 EFV 4 weeks after switch, with a reduction of 49.4% (IQR, 38.9–57.0%). As of 10 July, 2014, all of the 38 patients (100%) who had completed at least one follow-up of PVL achieved undetectable PVL (<40 copies/ml) following switch to a reduced dose of EFV after a mean observation of 13 weeks (IQR, 7–15 weeks).ConclusionsSwitch to cART containing a half tablet of EFV (1/2#) in HIV-positive Taiwanese patients with higher plasma EFV concentrations who had achieved viral suppression could maintain successful viral suppression with the guidance of TDM.

A simple, rapid, economical, and practical method for the determination of efavirenz in plasma of Chinese AIDS patients by reverse phase high-performance liquid chromatography with ultraviolet detector.

This study aimed to develop a reverse phase high-performance liquid chromatographic (RP-HPLC) method for the determination of efavirenz in human plasma and to use it for determining the concentrations of efavirenz in Chinese AIDS patient. A simple mobile phase consisting of 0.01 mol/L NaH2PO4 solution and acetonitrile (38:62, V/V) was pumped at a flow rate of 1.0 mL/min through a reverse phase Diamonsil C18 column maintained at 30°C. Diazepam was used as an internal standard and monitored with efavirenz at 247 nm. The protein of 100 μL plasma sample was precipitated before 20 μL of the supernatant was directly injected into the column. The linear response over the concentration ranges 0.10-20.0 μg/mL was obtained and the linear regression equations was Y = 2.2873X ‒ 0.1449 (r = 0.9999). The intra-day and inter-day precisions (1.9-2.6%, 2.2-7.2%, respectively), the relative and absolute recovery (99.3-106.3%, 75.6-80.3%, respectively) met the international standards. Stability of plasma samples were evaluated for short-term (ambient temperature for 16 h) and long-term (-20°C for 30 days) storage conditions and were found to be stable. The mean plasma concentration of efavirenz of the 406 patients was 2.21 ± 1.95 μg/mL, 77.3% of which were within the therapeutic window (1-4 μg/mL), 15.1% were below the window, and 7.6% were over it. In conclusion, the method had advantages of convenience, rapidity, necessary accuracy and precision, high practicality and met the needs for therapeutic drug monitoring and the pharmacokinetic study of efavirenz, especially in underdeveloped countries. For Chinese AIDS patients, it was beneficial to use efavirenz under the guidance of therapeutic drug monitoring.

Seradyn Quantitative Microsphere System Lamotrigine Immunoassay on a Hitachi 911 Analyzer Compared With HPLC-UV

Lamotrigine (LTG) is used currently as monotherapy or, more frequently, as add-on therapy with other antiepileptic drugs. It demonstrates efficacy against partial seizures, primary and secondary tonic clonic seizures, absence seizures, and drop attacks. LTG pharmacokinetics is complicated by coadministration with other antiepileptic drugs such as valproic acid, phenytoin, or carbamazepine. The wide interpatient variability in LTG dosage required to attain therapeutic plasma LTG concentrations for seizure control suggests that LTG is a good candidate for therapeutic drug monitoring (TDM). In this study, we compared the quantitative microsphere system (QMS) LTG immunoassay with the LTG high-performance liquid chromatography-ultra violet (HPLC-UV) assay routinely employed for TDM in our laboratory. Samples tested by these methods were patient samples presented for TDM and from a quality assurance program. Quality control material demonstrated within- and between-run (n = 6) coefficient of variation and biases of less than 10%. Patient samples demonstrated a Deming regression of QMS = 1.09 HPLC-UV - 0.17 and quality assurance program samples had a Deming regression of QMS = 1.03 HPLC-UV - 0.11. Patient samples demonstrated a mean bias of 6.1% and quality assurance program samples had a mean bias of 0.2%. The QMS LTG assay had a clinically small but significant overestimation of plasma LTG concentrations. It may be useful as a convenient alternative method that would provide TDM guidance if a chromatographic assay was not available.