Dolutegravir reaches the cerebrospinal fluid at about 0.15% of plasma levels, and exposure fell with higher BMI

Design

Population pharmacokinetic modelling with sparse plasma and cerebrospinal fluid sampling

Population

121 adults with HIV on dolutegravir 50 mg daily, mean BMI 32.2 kg/m2

Primary outcome

Plasma-to-cerebrospinal fluid equilibration and relative cerebrospinal fluid exposure

Effect

Equilibration half-life 1.82 h; cerebrospinal fluid-to-plasma coefficient 0.0015; AUC vs BMI r = -0.34

This population pharmacokinetic study sampled 121 adults with HIV, predominantly overweight or obese (mean BMI 32.2), who were taking dolutegravir 50 mg daily and had previously received antiretroviral therapy. Plasma concentrations fitted a one-compartment model with first-order absorption and elimination, with apparent oral clearance of 1.38 L/h per 70 kg.

For cerebrospinal fluid, the model estimated an equilibration half-life of 1.82 hours and a cerebrospinal fluid-to-plasma partition coefficient of 0.0015, meaning cerebrospinal fluid levels were about 0.15% of plasma levels at steady state. Estimated 24-hour exposure showed a moderate inverse correlation with BMI (r = -0.34).

A model of drug levels is not a clinical outcome. The study does not show that central nervous system efficacy is inadequate or that dose should change with body weight; dolutegravir is largely protein-bound, and cerebrospinal fluid concentration is a proxy for brain exposure. It adds exposure data in a population with high BMI.

• Dolutegravir cerebrospinal fluid levels were about 0.15% of plasma levels in this model.
• Exposure declined with higher BMI, but the correlation was moderate (r = -0.34).
• Do not change dolutegravir dosing on the basis of this study alone.
• Treat this as pharmacokinetic background for questions about central nervous system penetration.

Why it matters

It puts numbers on central nervous system exposure in a group where body size differs from the trials that set the dose.

Don't overread it

Cerebrospinal fluid concentration is a surrogate, and no efficacy or dosing outcome was tested.

The statistics, in plain English

A correlation of -0.34 means BMI explains only about one tenth of the variation in exposure. It is a tendency across the group, not a rule for an individual.

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