Steady-state concentration of venlafaxine enantiomers: model-based analysis of between-patient variability

OBJECTIVE: To investigate patients treated for depression with respect to steady-state concentration of venlafaxine enantiomers, to quantify within- and between-subject variability and to study the possible influence of individual characteristics such as gender and age. METHODS: Thirty-five inpatients received venlafaxine orally at a fixed 300-mg daily dose. Blood samples were taken on day 14 and day 28 for therapeutic drug monitoring purposes. All measurements reflected steady-state trough values. In a first stage, plasma concentrations of racemic venlafaxine (V) and O-desmethylvenlafaxine (ODV) were measured using a gas chromatography method. In a second stage, (+)/(-) enantiomeric ratios for V and ODV were determined using a stereoselective capillary electrophoresis method. RESULTS: Interindividual variability was 77% and 33% for concentrations of racemic V and ODV, respectively. Intraindividual variability was below 20% for both compounds. Enantiomeric ratios did not statistically differ from unity, with median (+)/(-) ratios of 1.14 for V and 0.97 for ODV. ODV/V metabolite formation ratios for the (+) and (-) enantiomers did not significantly differ from each other (median values 2.85 and 2.37, respectively). However, reduced ODV/V ratio for the (-) enantiomer was strongly associated with decreased (+)/(-) ratio for V (r(S)=0.71, P<0.001) and increased (+)/(-) ratio for ODV (r(S)=-0.79, P<0.001). In contrast, ODV/V ratio for the (+) enantiomer did not significantly correlate with parent compound (+)/(-) ratio and correlated only weakly with metabolite (+)/(-) ratio (r(S)=-0.38, P<0.05). When compared with males, females displayed a significantly lower ODV/V ratio for the (-) enantiomer (median values 1.42 vs 5.08 on day 14, P<0.05) but not for the (+) enantiomer (median values 2.36 vs 3.27, n.s.). Analysis did not reveal any significant association between ODV/V ratios and age, weight, height, creatinine clearance, smoking or co-medication. A pharmacokinetic model at steady state was developed that postulated two different enzyme systems to contribute to O-desmethylation. ODV(-) formation was supposed to largely depend on a single pathway, possibly impaired in a patient subpopulation. ODV(+) formation was postulated to rely on both pathways to a similar extent. Model predictions were in close agreement with observations in patients. CONCLUSION: Observations, together with model-based simulations, suggested that marked stereoselectivity in a patient subgroup may be related with impairment of O-desmethylation greater for (-) than (+) venlafaxine. This hypothesis requires testing against phenotypic and genotypic characteristics of patients.     

Distribution of venlafaxine and its O-desmethyl metabolite in human milk and their effects in breastfed infants

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desmethyl metabolite (ODV), in breastfeeding women taking venlafaxine for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Six women (mean age 34.5 years, mean weight 84.3 kg) taking venlafaxine (median dose 244 mg day(-1), range 225-300 mg day(-1)) and their seven infants (mean age 7.0 months, mean weight 7.3 kg) were studied. V and ODV in plasma and milk were measured by high-performance liquid chromatography over a 12 h dose interval at steady-state. Infant exposure was estimated as the product of estimated milk production rate (0.15 l kg(-1)day(-1)) and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/PAUC values of 2.5 (range 2.0-3.2) and 2.7 (range 2.3-3.2) were calculated for V and ODV, respectively. The mean maximum concentrations (95% CI) of V and ODV in milk were 1161 (95% CI, 588, 1734) microg l(-1) and 796 (362, 1230) microg l(-1). Mean infant exposure was 3.2% (1.7, 4.7%) for V and 3.2% (1.9, 4.9%) for ODV (as V equivalents). V was detected in the plasma of one out of seven infants studied (5 microg l(-1)), while ODV was detected in four of the infants, at concentrations ranging from 3 to 38 microg l(-1). All of the infants in the study were healthy, as reported by their mothers and/or by clinical examination on the study day. CONCLUSIONS: The concentrations of V and ODV in breast milk were 2.5 and 2.7 times those in maternal plasma. The mean total drug exposure (as venlafaxine equivalents) of the breastfed infants was 6.4% (5.5-7.3%), which is below the 10% notional level of concern. There were no adverse effects in any of the infants. The data support the use of V in breastfeeding. Nevertheless, since low concentrations of ODV were detected in the plasma of four out of the seven infants studied, we recommend breastfed infants should be monitored closely. Each decision to breast feed should be made as an individual risk:benefit analysis.     

Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting

When Efexor (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n = 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.     

Is the Measurement of Serum Formate Concentration Useful in the Diagnostics of Acute Methanol Poisoning? A Prospective Study of 38 Patients

The aim of this article was to study the role of serum formate (S‐formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 – median age 51 [interquartile range (IQR) 37–62] years with confirmed methanol poisoning. S‐formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S‐formate. Asymptomatic patients had median S‐formate of 1.9 (IQR 1.5–2.4) mmol/L. The median S‐formate was 15.2 (IQR 13.9–17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1–18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8–18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long‐term visual sequelae of poisoning had median S‐formate of 16.1 (IQR 14.3–19.9) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2–19.5) mmol/L. In lethal cases, the median S‐formate was 15.2 (IQR 13.8–15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S‐formate ≥17.5 mmol/L, S‐lactate ≥7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44–0.85 CI 95%) for S‐formate, 0.75 (0.56–0.93 CI 95%) for ‘S‐formate+S‐lactate’ and only 0.54 (0.38–0.69 CI 95%) for serum methanol, which is lower than for S‐formate (p < 0.05). The measurement of S‐formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S‐formate ≥3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S‐formate ≥11–12 mmol/L is associated with visual/CNS sequelae and a lethal outcome.     

Clinical relevance of deferasirox trough levels in β‐thalassemia patients

We evaluated the role of deferasirox therapeutic drug monitoring in order to avoid toxicity or treatment failure. Plasma concentrations, measured between two consecutive liver iron determinations, were determined at the end of dosing interval. Fifty‐four β‐thalassemic adult patients were enrolled: 50% were males; median age was 32.3 years (IQR 19.1‐41.7 years) and median body mass index was 22.25 kg/m² (IQR 20.24‐23.75 kg/m²). The mean deferasirox dose was 28.6 ± 6.3 mg/kg/d and mean plasma concentration was 17.3 ± 16.8 μg/mL. Drug levels showed lower results in males. Deferasirox concentration was significantly correlated with serum creatinine levels (P = .01) and serum ferritin (P < .0001). The assessment of deferasirox therapeutic drug monitoring could help clinicians to predict patient responses and to optimize the therapy.     

Therapeutic drug monitoring of ziprasidone in a clinical treatment setting

There is limited information on the pharmacokinetics ofziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Link?ping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20 -320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L(-1) mg(-1) d(-1) forZIPand SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively,with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for dose-normalized serum concentrations of ZIP, SMDZ, andSMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIPconcentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.     

Posaconazole trough concentrations are not influenced by inflammation: A prospective study

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1–2.9 mg/L, range 0.1–7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5–75 mg/L, range 0–457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P?=?0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.     

Free and glucuronidated olanzapine serum concentrations in psychiatric patients: influence of carbamazepine comedication

The influence of carbamazepine on the glucuronidation of the antipsychotic olanzapine was studied in a group of psychiatric patients. Steady-state serum concentrations of free and glucuronidated olanzapine were measured in 31 psychiatric patients in monotherapy (dose range, 2.5-30 mg/d; median, 15 mg/d) and in 16 patients being comedicated with carbamazepine (dose range, 5-50 mg/d; median, 20 mg/d). The concentrations were determined by HPLC with and without acid hydrolysis of glucuronidated olanzapine. For the monotherapy group, the concentrations of free and glucuronidated olanzapine ranged from 0 nmol/L to 292 nmol/L (median, 94 nmol/L) and from 0 nmol/L to 180 nmol/L (median, 27 nmol/L), respectively. The serum concentrations of the carbamazepine-treated group ranged from 21 nmol/L to 310 nmol/L (median, 81 nmol/L) and from 0 to 376 nmol/L (median, 57 nmol/L) for free and glucuronidated olanzapine, respectively. Two patients with outlying values were excluded from further analysis. The median concentration-to-daily dose ratios (C/D) of free and glucuronidated olanzapine in the monotherapy group were 5.8 nmol/L/mg and 2.2 nmol/L/mg, respectively (n =30). The corresponding values for the group comedicated with carbamazepine were 3.6 and 3.1 nmol/L/mg (n =15). Thus, the median C/D of free olanzapine in the carbamazepine group was 38% lower than that of the monotherapy group (P <0.01), confirming that carbamazepine accelerates the metabolism of olanzapine. Further, for the carbamazepine group the median glucuronidated olanzapine fraction constituted 79% of the free fraction compared with 43% for the monotherapy group (P <0.01), which suggests that an increased rate of olanzapine glucuronidation contributes to the increased rate of metabolism of olanzapine induced by carbamazepine.     

Immunosuppressive efficacy of tetrandrine combined with methylprednisolone against mitogen‐activated peripheral blood mononuclear cells of haemodialysis patients

Immunosuppressive therapy for prevention of acute rejection episode occasionally causes serious adverse effects, and thus it is important to develop new therapeutic approach for renal transplant recipients. This study evaluated the immunosuppressive pharmacodynamics of tetrandrine (TET) and/or methylprednisolone (MP) in haemodialysis patients in vitro by using the peripheral blood mononuclear cells (PBMCs) isolated from whole blood of haemodialysis patients. The median (range) of MP IC₅₀ values against the proliferation of patients PBMCs was 7.04 (2.30‐500.00) ng/mL. In contrast, the median (range) of MP IC₅₀ values against the proliferation of healthy PBMCs was 4.44 (3.19‐5.08) ng/mL. The median (range) of TET IC₅₀ values against the proliferation of patients PBMCs was 1.61 (1.04‐4.79) μmol/L. Lower concentrations of TET (0.3‐300 nmol/L) were able to decrease the IC₅₀ values of MP and thus potentiate the MP immunosuppressive effect on patient PBMCs. The median (range) of MP IC₅₀ values in combination with 0.3, 3, 30, and 300 nmol/L TET were 0.92 (0.49‐8.39), 2.10 (0.45‐20.00), 0.35 (0.092‐1.05), and 0.14 (0.05‐6.78) ng/mL, respectively. TET potentiates the MP immunosuppressive pharmacodynamics and thus, it was possible to use the combination of MP and TET to attenuate MP side effects. There were significant correlations between the IC₅₀ values of TET and stimulation indices (P=0.04, r=.58), the IC₅₀ values of TET and the haemodialysis periods (P=0.04, r=.57), or the IC₅₀ values of MP combined with 0.3 nmol/L TET and C‐reactive protein concentrations (P=0.04, r=.64), respectively.     

Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk

Aims To characterise the transfer of venlafaxine (V) and its O -desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast-fed infant.
Methods Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady-state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12  h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83  h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk×a milk intake of 0.15  l  kg⁻¹  day⁻¹ , relative to the weight-adjusted maternal dose.
Results Mean M/P for V was 4.1 (range 2.8–4.8) and 3.1 for ODV (range 2.8–3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7–9.2%) of the maternal weight-adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100  μg  l⁻¹ ) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects.
Conclusions These preliminary data show that the total dose of V and ODV ingested by breast-fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants' plasma. We recommend that exposed infants should be observed closely.     

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A retrospective study was conducted to assess our 10‐year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C_min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C_min was set between 2 and 7 mg/L (underexposure, C_min < 2 mg/L; overexposure, C_min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C_min. One thousand and forty‐nine patients had 2484 linezolid C_min assessed during treatment with conventional doses. Median (IQR) linezolid C_min was 5.08 mg/L (2.78–8.52 mg/L). Linezolid C_min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL_C‐G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124–1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL_C‐G estimates >100 mL/min. (OR 3.046; 95% CI 2.234–4.152, p < 0.001). Linezolid C_min was not correlated linearly with CrCL_C‐G (R² = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C_min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.     

Effect of cytochrome P450 enzyme polymorphisms on pharmacokinetics of venlafaxine

This study examines the relationship between blood concentrations of venlafaxine and its active metabolite, O-desmethyl venlafaxine (ODV), and genetic variants of the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human subjects. Trough blood concentrations were measured at steady state in patients treated with venlafaxine extended release in a clinical practice setting. CYP2D6 and CYP2C19 genotypes were converted to activity scores based on known activity levels of the two alleles comprising a genotype. After adjusting for drug dose and gender effects, higher CYP2D6 and CYP2C19 activity scores were significantly associated with lower venlafaxine concentrations (P < 0.001 for each). Only CYP2D6 was associated with the concentration of ODV (P < 0.001), in which genotypes with more active alleles were associated with higher ODV concentrations. The sum of venlafaxine plus ODV concentration showed the same pattern as venlafaxine concentrations with CYP2D6 and CYP2C19 genotypes with higher activity scores being associated with a lower venlafaxine plus ODV concentration (2D6 P = 0.01; 2C19 P < 0.001). Because allelic variants in both CYP2D6 and CYP2C19 influence the total concentration of the active compounds venlafaxine and ODV, both CYP2D6 and CYP2C19 genotypes should be considered when using pharmacogenomic information for venlafaxine dose alterations.     

CYP2B6 haplotype and biological factors responsible for hepatotoxicity in HIV-infected patients receiving efavirenz-based antiretroviral therapy

Data on the pharmacogenetic markers of CYP2B6 and biological factors associated with hepatotoxicity in HIV-infected patients receiving an efavirenz-based antiretroviral therapy (ART) regimen are very limited. A total of 134 HIV-infected Thai adults were prospectively enrolled to receive a once-daily regimen of efavirenz 600 mg/tenofovir/lamivudine. Seven single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped using real-time PCR. At 12 weeks after ART, plasma efavirenz concentrations at 12 h after dosing were measured. The mean ± standard deviation patient age was 37 ± 8 years, and 77.6% were male. The median (IQR) CD4 count was 43 cells/mm³ (17–105 cells/mm³). Eighteen patients (13.4%) had positive anti-HCV and 5 patients (3.7%) had positive HBsAg. The frequencies of heterozygous/homozygous mutants of each SNP were 64C>T (11%), 499C>G (0%), 516G>T (55%), 785A>G (63%), 1375A>G (0%), 1459C>T (3%) and 21563C>T (62%). The three most frequent haplotypes identified included *1/*6 (40.3%), *1/*1 (34.3%) and *6/*6 (8.2%). The median (IQR) plasma efavirenz concentration was 2.3 mg/L (1.4–3.7 mg/L). At 24 weeks, median (IQR) serum ALP was 98 mg/dL (73–133 mg/dL) and direct bilirubin was 0.11 mg/dL (0.10–0.19 mg/dL). The proportion of grade 1 and grade 2 elevated serum ALP was 12.7% and 1.5%, respectively. By multivariate analysis, factors associated with high ALP, total bilirubin and direct bilirubin included CYP2B6 haplotype *6/*6, high serum ALP at Week 0 and positive anti-HCV (all P < 0.05). In summary, HIV-infected patients with the pharmacogenetic marker ‘CYP2B6 haplotype *6/*6’ may have increased susceptibility to hepatotoxicity with efavirenz-based ART.     

Redefining the ACE-inhibitor dose-response relationship: substantial blood pressure lowering after massive doses

Objectives The blood pressure-lowering dose-response relationship for angiotensin converting enzyme (ACE) inhibitors is assumed to flatten at doses higher than those conventionally used in clinical practice. However, existing clinical trial data do not adequately address the haemodynamic effects of high ACE inhibitor dosages. Therefore, we examined the blood pressure responses in patients presenting to hospital following a deliberate ACE inhibitor overdose.Methods The study design was a retrospective case review, and included all patients who presented to our hospital in the past 5 years after an ACE inhibitor overdose. The data collected were heart rate and systemic blood pressure at various times after ingestion and maximum haemodynamic derangement; these were compared to baseline or recovered values.Results Data from 33 patients (24 men) were evaluated. The median (inter-quartile range, IQR) age of the patients was 49 years (IQR: 42–56 years). The median stated dose ingested was 140 mg (IQR: 60–280 mg), which is 20× (IQR: 7–42) the defined daily dose. The maximum fall in systolic blood pressure was 50 mmHg (IQR: 40–64 mmHg), diastolic blood pressure was 35 mmHg (IQR: 26–43 mmHg) and mean blood pressure was 39 mmHg (IQR: 30–47 mmHg).Conclusions The observed reduction in blood pressure following an overdose of an ACE inhibitor was greater than anticipated based on data from therapeutic doses. We conclude that a blood pressure-lowering dose-response relationship extends to higher ACE inhibitor doses than those conventionally used in clinical practice.     

Lamotrigine drug interactions in a TDM material

Using therapeutic drug monitoring (TDM) data from our laboratory, we have studied the concentration/dose relationship for lamotrigine and the influence of drug interactions in clinical practice. One hundred forty-nine lamotrigine samples from 104 adult patients were included in the study. The samples were collected as steady-state trough values, 9-16 hours after dose intake. Concomitant drug treatment was specified on the analysis request form. Lamotrigine serum concentrations were determined by high-performance liquid chromatography (HPLC). In 20 patients in monotherapy, the concentration/dose (C/D) ratio was 65 (range: 50-84) nmol/L/mg (mean and 95% confidence interval, antilog from lognormal distribution). In 37 patients with concomitant carbamazepine treatment, the C/D ratio was less than half that of the patients in monotherapy; 31 (2146) nmol/L/mg, and in 14 patients with phenytoin, it was even lower; 17 (13-23) nmol/L/mg. Valproic acid significantly increased the C/D to 251 (200-320) nmol/L/mg in 13 patients. Triple therapy with valproic acid and either carbamazepine or phenytoin (23 patients) yielded a C/D slightly above that of monotherapy, whereas a few patients on phenobarbital had a C/D slightly below that of monotherapy. The within-group C/D variation was comparatively small. The C/D ratio in a mixed lamotrigine TDM material shows a widespread intra- and interindividual variation, which can largely be explained by pharmacokinetic interactions with concomitantly used antiepileptic drugs. These results support the use of TDM in lamotrigine therapy.     

Ganciclovir treatment in children: evidence of subtherapeutic levels

Ganciclovir (GCV) is used to treat babies and older children with cytomegalovirus-related disease. Treatment courses are generally derived from adult studies and there are few data relating to the pharmacokinetics of GCV in children. In adults, low trough GCV levels have been associated with treatment failure and virological resistance. Data regarding suitable drug levels for use in therapeutic drug monitoring (TDM) in the paediatric age group do not currently exist. In this study, anonymised data for all GCV levels sent to the UK Antibiotic Reference Laboratory from 1 November 1999 to 31 March 2007 were reviewed and analysed by age group. In total, 339 specimens were received from 129 patients; 192 specimens were from patients aged <18 years. There were significantly more trough GCV levels <0.5 mg/L in those aged <6 months and 6-12 months compared with adults (64.8% and 53.9%, respectively, vs. 15.9%; P<0.001). Those aged 5-18 years also had significantly more trough samples with levels <0.5 mg/L (80.0% vs. 15.9%; P<0.001). There was a significant difference between median peak GCV levels in those aged <6 months and adults (4.8 mg/L vs. 5.7 mg/L, respectively; P=0.047). In conclusion, GCV levels associated with treatment failure and considered subtherapeutic in adult patients were observed more often in specimens from paediatric patients. These lower levels may have implications for dosing in the paediatric age group, particularly during periods of rapid change in renal function such as the neonatal period. Clinicians should be aware of the relatively low drug exposure noted in this study and consider TDM and increasing drug dose where virological response is poor.     

Quantitation of escitalopram and its metabolites by liquid chromatography‐tandem mass spectrometry in psychiatric patients: New metabolic ratio establishment

Therapeutic drug monitoring (TDM) is used to determine the concentration of drug in plasma/serum to adjust the dose of the therapeutic drug. Selective and sensitive analytical methods are used to determine drug and metabolite levels for the successful application of TDM. The aim of the study was to develop and validate using LC‐MS/MS to analyse quantitative assay of escitalopram (S‐CT) and metabolites in human plasma samples. In order to provide a convenient and safe treatment dose, it was aimed to determine the levels of S‐CT and its metabolites in the patients’ plasma. A new method with short sample preparation and analysis time was developed and validated using LC‐MS/MS to analyse quantitative assay of S‐CT and its metabolites in plasma. Also, plasma samples of 30 patients using 20 mg S‐CT between the ages of 18 and 65 years were analysed by the validated method. The mean values of S‐CT, demethyl escitalopram and didemethyl escitalopram in plasma of patients were 27.59, 85.52 and 44.30 ng/mL, respectively. At the end of the analysis, the metabolic ratio of S‐CT and metabolites was calculated. It is considered that the method for the quantitative analysis of S‐CT and its metabolites in human plasma samples may contribute to the literature on account of its sensitive and easy application. Additionally, the use of our data by physicians will contribute to the effective drug treatment for their patients who take S‐CT.     

Time course of clinical response to venlafaxine: relevance of plasma level and chirality

Objective Early clinical response to antidepressant treatment is an important therapeutic goal, considering the psychological, social and economic consequences of depression. The aim of the present study was to investigate the relationship between the time course of response and the concentration of venlafaxine (V), its active metabolite O-desmethylvenlafaxine (ODV) and enantiomeric ratios V(+)/V(–) and ODV(+)/ODV(–).Methods Depressed inpatients (n=35) received V orally at a fixed 300 mg daily dose. Accepted comedication included clorazepate (maximum 60 mg/day), zopiclone (maximum 15 mg/day) and low-dose trazodone (maximum 200 mg/day). Severity of depression was assessed on days 0, 4, 7, 11, 14, 21 and 28 (Montgomery and Åsberg Depression Rating Scale). Blood samples were taken on day 14 and day 28 and submitted to stereoselective determination. All measurements reflected trough steady-state values. First, pattern analysis was used to provide a categorical perspective of clinical response (50% improvement from baseline depression score). Patients displaying non-response, transient response, early persistent response and delayed persistent response were compared with respect to racemic concentrations and enantiomeric ratios. Second, in a dimensional perspective, mixed-effects modelling was used to analyse severity of depression versus time curves with respect to the possible influence of concentrations and enantiomeric ratios.Results Comparison of patients with and without persistent response did not reveal any significant difference for V, ODV, V+ODV plasma levels or enantiomeric ratios. Persistent response was significantly associated with less frequent pre-study antidepressant medication and less frequent comedication with zopiclone (day 14) and clorazepate (day 28) during the study. Focus on patients with persistent response (n=19, 54.3%) indicated that early response, first observed before day 14, was associated with significantly higher V+ODV concentration than delayed response (median 725 ng/ml versus 554 ng/ml, P=0.023). No difference was found for pre-study medication or comedication during the study. Shorter time to onset of response was significantly associated with lower V(+)/V(–) enantiomeric ratio (r_s=0.48, P<0.05). Mixed-effects modelling of depression severity versus time curves in patients with persistent response confirmed that either higher V+ODV plasma level or lower V(+)/V(–) ratio were significantly associated with more rapid decrease of depression score (likelihood ratio tests, P=0.012 and P=0.046, respectively).Conclusion Considering its modest sample size, naturalistic design and limited observation period, the present study provided preliminary indication that earlier clinical response may occur with higher V+ODV plasma level, extending previous dose-response studies. The hypothesis was also raised that exposure to a more potent noradrenergic therapeutic moiety, as reflected by a lower V(+)/V(–) ratio, may be relevant to early improvement of depression.     

Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity

The present study was undertaken to investigate thoroughly the preclinical psychopharmacological profile of venlafaxine, testing a wide range of doses in animal models indicative of antidepressant-like effects. Venlafaxine was found to be active in mouse forced swimming test (at 8, 16, 32 and 64 mg/kg) and to increase spontaneous locomotor activity (at 16, 32 and 64 mg/kg). Venlafaxine antagonised apomorphine-induced (16 mg/kg) hypothermia (at 2, 4, 8, 16, 32 and 64 mg/kg). Pretreatment with PCPA significantly attenuated the anti-immobility effects of venlafaxine (8 and 16 mg/kg; P < 0.01) in the mouse forced swimming test. Venlafaxine at a dose of 32 mg/kg remained active, despite PCPA pretreatment. DSP-4 significantly attenuated the anti-immobility effects of venlafaxine (16 mg/kg; P < 0.05), whereas venlafaxine at 32 mg/kg remained active, despite DSP-4 pretreatment. Venlafaxine was active in the forced swimming test when administered at sub-effective doses in combination with (±) pindolol (venlafaxine: 1 and 2 mg/kg), RU 24969 (venlafaxine: 1, 2 and 4 mg/kg), 8-OH-DPAT (venlafaxine: 4 mg/kg), clonidine (venlafaxine: 1, 2 and 4 mg/kg), lithium (venlafaxine: 1, 2, and 4 mg/kg) and quinine (venlafaxine: 1 and 2 mg/kg). Prior administration with NAN-190 antagonised the anti-immobility effects of venlafaxine (8, 16 and 32 mg/kg). Interaction studies did not induce changes in locomotor activity. The results of the present study indicated that, at low doses, venlafaxine inhibited serotonin reuptake, while at higher doses it inhibited both serotonin and noradrenaline reuptake. Received: 19 May 1997/Final version: 1 December 1997