Case studies for therapeutic drug monitoring (TDM)
Simon Collins, HIV i-Base
The clinical utility of therapeutic drug monitoring (TDM) was discussed at the meeting in a special roundtable session with HIV clinicians and pharmacologists using several real patient cases. As well as highlighting the complexity of most cases, the forum also provided a timely opportunity to discuss clinical scenarios where TDM may be most useful in supporting patient management.
Discussion of clinical management highlighted the importance that summary case notes often provided insufficient detail, but nevertheless, even when pressed to play ‘devil’s advocate’ the strength with which some panel members refused to use the information provided by TDM was somewhat surprising.
The first case was whether TDM would be useful for a 28-year-old woman, on first-line therapy for 14 months with d4T/3TC/NVP, who weighed 52kg and who has just developed raised liver enzymes.
In order to provide an answer the level of enzyme elevation needed clarification because it is unusual for levels to only increase after such a long otherwise stable period. Where TDM is not available, and levels were seriously elevated, switching nevirapine to a protease inhibitor was thought reasonable by most panel and audience members – but in practice this is likely to have a significant impact on quality of life for the patient in terms of pill count and side effects.
Detailing the case further, TDM was performed, and nevirapine levels were found to be elevated: did panel members think this would change the utility of TDM?
For David Burger, this provided very useful information. Previous studies, including presentations at this workshop, have highlighted the fact that women, particularly patients with low weight, are at increased risk of toxicity with nevirapine and are likely to experience higher drug levels. TDM is routinely used for all patients using PI or NNRTI-based combinations in the Netherlands, so if this patient were treated in Nijmegen and found to have very high drug levels, Dr Burger would feel confident in carefully adjusting the dose and checking the new level.
Jonathan Shapiro said that even if drug levels were five times higher than the recommended trough of 3.4mg/L, he would not feel confident in adjusting the nevirapine dose – citing nevirapine’s low genetic barrier to resistance. He would prefer to change to a protease combination rather than use TDM to achieve and manage treatment at lower drug levels.
A second case was that of an African-American woman, who weighed 130kg, and who was treatment naïve when starting d4T/3TC/lopinavir/r five months ago with a baseline viral load of 80,000 copies/mL. Her viral load after four months was 3,000 copies/ml and is now 3,200 copies/mL.
Here there was general consensus over patient management, and concern that viral load was not checked after the first month. Most clinicians would have hoped to pick up a failing treatment much earlier. Adherence was a possible explanation, as was pre-existing resistance that could have prevented the patient from benefiting from three fully active drugs.
Abbott researchers confirmed that drug clearance could be affected by weight but that this would only be expected with extremely light or heavy individuals, but also that a weight-related response was not seen in registrational studies of lopinavir/r.
Although weight impacts volume distribution, this is based on lean body mass. Peaks may be lower and troughs higher but this may not a priori be due to weight.
When either high or low weight is an issue for drug absorption, this presents a very good case for TDM, said Courtney Fletcher who would perform the intervention much earlier at two weeks into therapy – after drug levels have achieved steady-state but when any changes can also have an immediate effect. Genotype and TDM would be used together to prevent failure and protect the first combination.
The final example was that of a 54-year-old male smoker with a family history of heart disease who is on a third-line regimen containing lopinavir/r and who has cholesterol levels above NCE threshold.
Switching to a non-PI based regimen is unlikely to be possible due to previous resistance but there was a general consensus on the importance of multiple approaches: diet; exercise; stopping smoking, perhaps with Zyban: statin treatment – after checking for interactions for both Zyban and statins and lopinavir/r; consideration of switching to atazanavir – with an eye on previous resistance – and the approach here might be different depending on whether the patient was currently virally suppressed.
This is a real-life situation that is increasingly common. In this case TDM showed he had high trough levels of lopinavir/r, and with the support of TDM together with dietary changes and exercise, he was able to reduce the lopinavir/r dose to 2x400mg capsules BID, and still maintain trough levels >4.0mg/L.
Researchers from Abbott suggested confirming the phenotype prior to changing a dose for treatment experienced patients in case the higher level was needed, and they also suggested that there was unlikely to be a clinically relevant interaction with Zyban – a previous case study had shown no increased risk of compulsion when used with lopinavir/r – although closer monitoring would be prudent.
In summary, these discussions were as interesting from the approaches to patient management as well as the specific interpretation of information from TDM, in modifying dosing while maintaining efficacy – resulting in improved and safe choices for patients. Some clinicians still remain unconvinced – but these real-life examples suggested to many others that there were practical benefits that become available with the additional information that TDM provides.
Roundtable discussion: clinical implications of TDM. 4th Intl Workshop on Clinical Pharmacology of HIV Therapy, Cannes 27th-29 March 2003.
What was perhaps most enlightening about this round table discussion was the division of opinion between American physicians and the Europeans on the potential usefulness of TDM. However, in this debate the UK sided with the French, Dutch and Germans in feeling that it provided yet another important piece of data in conjunction with genotyping, adherence support etc to assist clinical decision making. Clearly more prospective studies on the clinical utility of TDM are required.