Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

BACKGROUND: People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric side effects may present at a higher frequency in patients with higher dolutegravir serum concentrations. METHODS: We performed a retrospective analysis of our therapeutic drug monitoring registry identifying patients receiving once-daily dolutegravir without concomitant interacting drugs and significant clinical conditions. Data were analysed stratifying time after drug dose intake (maximum concentration 0.5-4 and trough concentration 21-27 h). Cerebrospinal fluid samples from patients enrolled in neurological studies and receiving dolutegravir were analysed for dolutegravir cerebrospinal fluid concentrations and cerebrospinal fluid-to-plasma ratios. Serum and cerebrospinal fluid concentrations were measured through validated chromatographic methods. RESULTS: We included 207 (providing 457 serum samples) and 41 patients (providing 41 cerebrospinal fluid samples). Participants were mostly male (68.2-72.8%) of median age of 50 years (50-53 years). Non-significant changes in dolutegravir maximum concentration and trough concentration were observed with age at Spearman's test (p values > 0.05); linear logistic regression showed a significant effect of age on dolutegravir trough concentration (p = 0.0013) (Fig. 1). Dolutegravir maximum concentration [3830 ng/mL (2311-5057) vs 4230 ng/mL (2919-5272), p = 0.311] and trough concentration [838 ng/mL (362-1587) vs 966 ng/mL (460-2085), p = 0.056] were non-significantly or borderline higher in patients aged > 50 years. Cerebrospinal dolutegravir concentrations were associated with plasma concentrations (ρ = 0.374, p = 0.016) and age (ρ = 0.537, p = 0.003); cerebrospinal fluid dolutegravir concentrations (13.8 vs 7.3 ng/mL, p = 0.015) and cerebrospinal fluid-to-plasma ratios (0.57 vs 0.32%, p = 0.017] were higher in participants aged > 50 years. CONCLUSIONS: We observed an increase in dolutegravir exposure in serum and in cerebrospinal fluid in older patients living with human immunodeficiency virus.

An LC/ESI-MS/MS method to quantify the PI3K inhibitor GDC-0084 in human plasma and cerebrospinal fluid: Validation and clinical application.

A liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method was developed and validated to measure GDC-0084 in human plasma and cerebrospinal fluid (CSF). Reverse-phase chromatography with gradient elution was performed using a C18 column (50 × 2.0 mm, 3 µm). Solid-phase extraction of plasma and CSF was employed to give excellent recovery. MS detection was performed with positive ion screening in multiple reaction monitoring mode. The precursor to the product ions (Q1 → Q3) selected for GDC-0084 and GDC-0084-d6 were 383.2 → 353.2 and 389.2 → 353.2, respectively. A separate calibration curve was established for human plasma and CSF. Both calibration curves, ranging from 0.2 to 200 ng/mL, were linear and had acceptable intra- and inter-day precision and accuracy. The lower limit of quantitation and limit of detection for GDC-0084 in human plasma were 0.2 ng/mL (signal/noise ≥47) and 0.005 ng/mL (signal/noise ≥3.5), respectively, and for GDC-0084 in human CSF were 0.2 ng/mL (signal/noise ≥19.7) and 0.04 ng/mL (signal/noise ≥7.2). This method was successfully applied to analyze serial plasma samples obtained from children with diffuse intrinsic pontine gliomas and other midline gliomas who participated in pharmacokinetic studies as part of a phase I clinical trial of GDC-0084.

Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy.

Efavirenz, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, is a promising addition to the antiretroviral armamentarium. Efavirenz levels and HIV-1 RNA levels were measured in cerebrospinal fluid (CSF) and plasma of 10 HIV-1-infected patients taking efavirenz, 600 mg daily, in combination with other antiretroviral medications. Efavirenz was detected in the CSF at a mean concentration of 35.1 nM (range, 6. 6-58.9 nM), which was above the IC95 for wild-type HIV-1. The mean CSF-to-plasma ratio was 0.61% (range, 0.26%-0.99%). CSF HIV-1 RNA levels were ascertained in 9 of the patients; all were <400 copies/mL after a mean of 26 weeks on therapy. Eight of the 9 patients had no detectable virus in plasma. These results indicate that efavirenz is present in the CSF at low levels and is effective in suppressing CSF viral levels when used in combination therapy.

Diffusion of ofloxacin into the cerebrospinal fluid in patients with bacterial meningitis.

Ofloxacin diffusion into cerebrospinal fluid (CSF) was evaluated in nine patients with bacterial meningitis. Patients were under treatment with i.v. amoxicillin (100 mg/kg/day), and during the first five days they were also given oral ofloxacin, 200 mg b.i.d. On days 2 and 5, blood and CSF samples were collected for assays by both HPLC and microbiological techniques. Samples were obtained 2 h (n = 2), 4 h (n = 1), 6 h (n = 2), 8 h (n = 2) and 12 h (n = 2) after the ofloxacin dose respectively. Concentration in CSF was 50 to 60% of that in serum and there was no significant difference between results with the two assay techniques.

Study of the cerebrospinal fluid penetrability of ofloxacin.

In patients with different neurological diseases with blood-brain barrier dysfunction subjected to diagnostic CSF-tap, simultaneous determinations of ofloxacin concentrations in serum and in CSF were carried out. The results show that ofloxacin penetrates well into the CSF achieving adequate bactericidal concentrations against most of the common causative pathogens of meningitis.