Pharmacokinetics and further benefits of therapeutic drug monitoring (TDM)
Simon Collins, HIV i-Base
TDM to individualise indinavir/ritonavir dosing
TDM is routinely used in France for dual-PI combinations and patients in France have anecdotally been using lower dual-PI doses for many years on the basis of the results provided. Guiard-Schmid and colleagues retrospectively reviewed 153 patients using low dose ritonavir (RTV) with three doses of indinavir (IDV) from June 1999-December 2001. 
Forty-two patients were treatment naïve and starting their first therapy, 72 were switching dosing only from previous TID indinavir regimen, and 39 were changing to IDV/RTV as part of a new rescue therapy. All patients received 100mg RTV BID. Physician choice determined original IDV dose: 800mg BID (Group 1, 57%), 600mg BID (Group 2, 37%), 400mg (Group 3, 6%).
After a mean 13 months (± 6.8mo) duration of treatment and a median of three (1-9) IDV drug level samples, only 19% patients remained on the 800/100 BID dose. Dose reductions due to side effects and a high Cmax >10000 ng/ml, were performed in 70 patients (55 from Group 1, 14 from Group 2). 73% of naïve patients, 80% of switch and 31% of salvage patients had viral load <50 copies/ml at last test. Additionally, 14/27 patients with viral rebound on IDV TID prior to the switch recovered viral load <50 copies/ml.
Using TDM to individualise therapy in France appears to improve toxicity profile of the dual-PI combination and retain efficacy at lower doses to those generally recommended.
Food interaction with indinavir/ritonavir
A small study from Burger and colleagues in the Netherlands, similarly concerned with the higher Cmax and shorter Tmax of the 800mg/100mg indinavir regimen, analysed the PK effect of food in patients at steady-state dosing.  They report that taking RTV/IDV on an empty stomach increased Cmax by 19% without significantly affecting Cmin or AUC, and that neither the Cmin or AUC were adversely affected when taken with food. The recommendation for patients remaining on the 800/100 dose was therefore to take these medications with a light meal.
TDM for amprenavir/ritonavir
The relationship between amprenavir (APV) Cmin when given in combination with ritonavir and virological response was reported by Peytavin in a substudy from the Genophar Study which guided treatment choice by genotype.  A statistical relationship between Cmin at week 8 (though not at week 12) and both viral load at week 12 and change in viral load between weeks 0-12.
APV cut-off of 1250ng/ml was the best predictor of virological response (Spearman test, p=0.02) and IQ combining APV Cmin and mutation score were highly predictive of virological response at week 12.
TDM for lopinavir/r and amprenavir (and NNRTIs)
The interaction between amprenavir and ritonavir is complicated when using lopinavir, and further complicated when additional NNRTIs are included in a regimen. Yet these combinations are increasing used in salvage therapy, and review of these interactions from Reynolds and colleagues from Liverpool University again highlighted the utility of TDM. 
Adding LPV/r to APV/r resulted in a significant decrease in the median APV plasma concentration (p=0.05) despite an increase in APV dose. In a small cohort, the addition of an NNRTI further reduced the median APV concentration (p=0.03). LPV median plasma concentrations were significantly reduced by adding APV (p=0.005). However, the presence of an NNRTI had a lesser effect (p=0.22).
|APV concentrations (ng/ml)|
|LPV concentrations (ng/ml)|
|LPV 400/RTV100+ NNRTI||8||4683||667-18892|
* 600-1200mg BID
The study concluded that is a complex PK interaction and given the marked interpatient variability highlights the potential importance of concentration monitoring (TDM).
TDM for newly reported interaction between lopinavir/r and nevirapine
A clinically significant interaction between lopinavir/r and nevirapine was reported by Degen and colleagues from Hamburg. Steady-state levels of LPV/r and concomitant NNRTIs were measured by liquid chromatography/mass spectrometry for efavirenz (n=4), nevirapine (n=2) and LPV/r without NNRTI (n=4). 
|No NNRTI||5690 (1420-11200)||124000 (3920-17300)||3.5h (1-12)|
|EFV||7625 (2870-11200)||14100 (6990-17300)||3.5h (2-12)|
|NVP||3330 (1420-5240)||8110 (12300-3920)||N/p|
Compared to the EFV group, NVP pts. showed a 57% lower median Cmin and 43% lower median Cmax. In patients without NNRTI the median Cmin was 25% and Cmax 15% lower than in the EFV. The PK of NVP showed an 80% decrease of median Cmin and 77% of median Cmax compared with published data without LPV/r.
This study size, although tiny, shows the importance of individually monitoring drug levels for patients whenever interactions show a high degree of variability even when they have previously been well described. LPV/r levels were within an optimal range for all patients but suggest an increased dose of nevirapine and possibly a reduced efavirenz dose based on individual results. The study concluded that the results supported the use of TDM in clinical practice.
- JB Guiard-Schmid, AH Gbadoe, JM Poirier et al – Efficacy and safety of indinavir/ritonavir combination in the era of pharmacological monitoring. XIV International AIDS Conference, Barcelona, 7-12 July. Abstract TuPeB4577.
- R Aarnoutse, J Wasmuth, G Fätkenheuer et al – Indinavir/ritonavir 800/100mg twice daily (BID) should be taken with food to prevent toxic indinavir peak plasma levels. XIV International AIDS Conference, Barcelona, 7-12 July. Abstract TuPeB4570.
- G Peytavin, C Lamotte, A G Marcelin et al. Predictivity of amprenavir plasma concentrations on virological response in HIV-infected patients treated with amprenavir/ritonavir containing regimen: a Genophar substudy. XIV International AIDS Conference, Barcelona, 7-12 July. Abstract TuPeB4571.
- O Degen, M Kurowski, J van Lunzen et al. Steady state pharmacokinetic (PK) of Lopinavir (LPV) in combination with nevirapine (NVP) or efavirenz (EFV). XIV International AIDS Conference, Barcelona, 7-12 July. Abstract TuPeB4573.
- HE Reynolds, SE Gibbons, JF Tjia et a.- The pharmacokinetic interaction of lopinavir/ritonavir and amprenavir in clinical practice. XIV International AIDS Conference, Barcelona, 7-12 July. Abstract TuPeB4560.