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SIMPLIFYING THERAPEUTIC
DRUG MONITORING FOR TWICE DAILY REGIMENS OF KALETRA
Christopher S Alexander1,2,
Julio SG Montaner1,2, Jérôme Asselin1, Lillian
Ting1, Kelly L McNabb1, Marianne Harris1, Silvia
Guillemi1,2, P Richard Harrigan1,2
1British Columbia Centre for Excellence in HIV/AIDS; 2University
of British Columbia, Faculty of Medicine, Department of Medicine
Objectives:
Reliable characterization of the pharmacokinetics (PK) of lopinavir (LPV) involves
the collection of multiple blood samples at regular timed intervals over the
entire dosing period. Both cost and inconvenience severely limit the application
of this approach to therapeutic drug. In this retrospect study, we demonstrate
that LPV exposures to can be estimated based on plasma concentrations measured
at 2 and 6 hours after drug administration.
Methods: The PK of LPV was characterized for 112 patients on
salvage therapy including twice daily Kaletra (3 or 4 capsules). After a minimum
of 2 weeks on a stable regimen, blood was drawn immediately before and every
2 hours for 12 hours after a timed, observed medication dose. Plasma concentrations
of LPV and ritonavir (RTV) were then determined by a sensitive validated HPLC-MS-MS
assay. Key PK parameters (AUC0-12, Ctrough) derived from
these analyses were entered into a forward selection linear regression model
designed to find the best correlation with LPV concentrations to a maximum of
two distinct time points. Jackknife standard deviations (s)
were determined.
Results: Patients were taking a median 5 (IQR: 4-6) antiretrovirals
including at least one other PI or NNRTI. Significantly, 86 (76%) patients were
concurrently taking an NNRTI or APV. The median steady state evening troughs
(C12h) and AUC(0-12) were 3760 ng/mL (IQR: 2230-5570)
and 67,400 h*ng/mL (IQR: 51,400 - 88,800) respectively for LPV. In linear regression
analyses, the AUC0-12 was best correlated (r2= 0.96) to
plasma LPV concentrations measured at 2 and 6 hrs with a Jackknife s
of 6530. A single plasma concentration at 10h was best correlated with C12h
(r2= 0.91, s
= 846) with no significant improvement with additional data.
Conclusions: AUC0-12 for LPV can be accurately estimated
from 2 plasma samples collected at 2 and 6 hours after administration of the
dose.