Lopinavir suitable for TDM

The use of therapeutic drug monitoring (TDM) for selected patient groups (interactions of new drugs, in treatment experienced patients, hepatitis coinfection, children etc) has allowed individualised dosing for both single and boosted PI-based regimens in some clinics in the UK and has widespread use in the Netherlands and France.

Although ritonavir-boosted levels of lopinavir were initially thought to produce trough levels safely exceeding the IC90 reducing the utility of TDM, inter-patient variability has shown that a few patients still absorb suboptimal levels.

One of the requirements for TDM to be safely used to recommend individualised dose adjustments, is the accuracy of any single measurement, and that drug levels within each patient – intra-patient variability – also remain relatively stable and consistent. This accuracy in a clinical setting is also determined by accuracy of recorded timing and patient variability of drug and food intake.

Ideally, for lopinavir/r, samples should be taken both at 12-hour post dose, (which for this drug may not be the actual trough as levels continue to drop post dose due to a short delay in absorption) and two-hours post observed dose.

Martha Boffito and colleagues from Liverpool University reported in the 2 May issue of AIDS on the intra-individual variability of lopinavir trough concentrations (Ctrough) prospectively measured by validated LC-MS in 25 HIV-positive out-patients (22 men, three women; median age 42 years, range 29-51), over a median period of 18 months (range 14-22). Blood samples were measured before the morning dose. One hundred and forty-three samples were analysed (5-9 for each patient).

Median lopinavir Ctrough considering all 25 patients ranged from 1,832 to 11,362 ng/ml (median 5,365). The median coefficient of variation of intra-patient variability was 35% (range 15-54).

Use of treatment was mixed (three were on first treatment, seven on second and 15 were multi-experienced). The median baseline CD4 was 204 cells/mm3 (range 94-433) increasing to 280 cells/mm3 (range 170-601) at the end of follow-up. Median plasma HIV-RNA level was approximately five logs (range 6,900-1,000,000) at baseline and was <50 copies/mL in 16 out of 25 subjects at the end of follow-up; the remaining nine subjects had a median viral load of 620 copies/ml (range 100-7900).

In this study, the authors’ report that the variability determined for lopinavir, when co-administered with ritonavir in Kaletra, is of the same order of magnitude as that previously reported for nelfinavir and amprenavir when administered without ritonavir boosting. Consequently, even only a few determinations of plasma concentrations may be representative of individual exposure to PI, and may thus form the basis for dose adjustment.

Boffito M, Back DJ, Hoggard PG – Intra-individual variability in lopinavir plasma trough concentrations supports therapeutic drug monitoring. AIDS 2003; 17(7):1107-1108

Comment

Double PI combinations including lopinavir/r are another appropriate area for TDM. The most prominent example is the combination with amprenavir. In patients with partial resistance, TDM can be used to achieve higher trough levels and using the virtual phenotype approach to determine a virtual IQ may make sense. Patients with impaired liver function are another subset for use of TDM.