Clinical Pharmacology of Antiretroviral Therapy, Liverpool, UK , March 2001

Report by Polly Clayden, HIV i-Base

Intended as a primer in the run up to Noordwijk, and rather under publicised, the Clinical Pharmacology of Antiretroviral Therapy meeting in Liverpool turned out to be a real gem.

The meeting’s remit was to examine basic pharmacology issues in relation to caring for HIV-positive patients and included some interesting PK non-specific but related presentations.

Pharmacokinetic principles

After being presented by Ceppie Merry as ‘One of the few people in the world of pharmacology that needs no introduction’ David Back began by explaining basic pharmacokinetic principles [1], or ‘What we actually need to know when we are prescribing’. He emphasised the importance of pharmacokinetics in relation to ART:

When designing dosing regimens – ‘one dose for all’ is not clear cut
For individualisation of therapy particularly for children, IVDU and people with liver impairment
For patients not responding to therapy
When a drug is causing toxicity
When dealing with interactions

He outlined the different issues for each class of drugs. For example that in general NRTIs are well absorbed and that it is intracellular phosphorylation that determines the efficacy of each drug. But that it is particularly in relation to PIs and NNRTIs that pharmacokinetics has become an unavoidable consideration for anyone involved in treating HIV successfully.

Professor Back explained that this is ‘þprimarily because of the considerable inter and intra-individual variability in plasma concentrations and the marked potential for drug interactions leading to reduced or elevated PI concentrations, which can be potentially sub-therapeutic or will predispose to adverse events’. He proposed that therapeutic drug monitoring (TDM) could both ensure that patients maintain a PK profile well above the IC50 or IC90, and could also be important in detecting inappropriately high plasma concentrations of a drug which in turn could lead to toxicity.

Factors affecting the rate of an individual’s drug absorption include food, other medications and the disease itself. Another major factor is the role of transporter proteins; p-glycoprotein and multidrug resistant protein can actively extrude PIs from cells. The role of p-gp and multi drug resistant protein in lymphocytes is currently the subject of much research.

He remarked that p-glycoprotein had recently even hit the popular press – Time magazine had devoted column inches to the subject of ‘transporters’ and that The Times had announced that ‘genetic make up effects therapy’. He briefly discussed the increasing importance of the role of pharmacogenetics in future optimal individual prescribing, leaving many question marks over the principle of ‘one dose for all’.

Antimicrobial pharmacokinetics

Despite the Duesbergism that we ‘can’t apply laws of antibiotics to antiretrovirals’ Dr Michael Postelnick from Northwestern Memorial Hospital in Chicago, made some interesting observations from findings with PK of anti-infectives and the relationship to therapeutic outcomes [2].

He explained that antibiotic killing of bacteria can either be ‘concentration dependent’ in which higher peak concentrations result in more rapid and more complete killing or ‘time dependent’ where eradication of bacteria depends on the amount of time the bacteria is exposed to concentrations above the organisms MIC. In addition the area under the inhibitory curve (AUIC) has also been shown to be predictive of successful clinical outcome.

Dr Postelnick gave some examples – the antibiotics, aminoglycosides are concentration-dependent and require peak concentrations of eight times the MIC or above to achieve optimal cure rates. Floroquinolones are also concentration-dependent with peak MIC ratios of ten to twelve being associated with bacterial eradication and low likelihood of resistance development, while AUICs of 125 to 250 are associated with successful therapy. Beta-lactums and glycopeptides are time- dependent antibiotics. He showed that sub-optimal AUICs have also been associated with the development of resistance and emphasised the need to use dosage optimisation strategies, such as measuring concentrations, in order to avoid this. He concluded ‘With the tools we have now, the use of pharmacology (applied to HIV treatment), should help us greatly.’

Drug interactions, treatment failure and adverse drug reactions

To add to the arguments as to why we should consider pharmacokinetics and their role in optimising treatment, four presentations looked at some related factors. Dr Frank Palella presented his much-quoted HOPS data illustrating the limited time on first and then subsequent HAART regimens reported from his cohort [3].

Dr Veronica Miller examined the role of resistance and resistance testing and their relationship to treatment success or failure [4]. Dr Munir Pirmohamed looked at the complexities of HIV and adverse drug reactions particularly hypersensitivity and the lipodystrophy syndromes [5]. And Dr John Gerber explained some of the issues involved with potential drug-drug interactions in the use not only of complex HAART but also concomitant medications [6].

Pharmacological aspects of treatment failure

Dr Saye Khoo’s presentation on the pharmacological aspects of treatment failure again emphasised that treatment failure is multifactorial and includes the development of drug resistance, inadequate drug potency, lack of adherence or pharmacological factors such as low plasma levels and poor penetration into sanctuary sites [7]. He remarked that ‘Pharmacological reasons and adherence drive development of resistance and this is important because you can do something about it fairly early on’.

There is a growing body of data to link low plasma levels of PIs and NNRTIs with HIV treatment failure. Dr Khoo suggested that the instance in the clinic of sub-therapeutic drug levels (below the IC50 for wild-type HIV, corrected for plasma protein binding) is probably far greater than is generally appreciated. In addition, thresholds based on the sensitivity of wild type HIV are not appropriate for people who have already failed therapy and therefore may have accumulated resistance.

The role of pharmacology and TDM in optimising outcome

Dr’s Ceppie Merry and Richard Hoetelmans discussed the role of pharmacology and TDM in the clinic [8, 9]. Dr Merry referred to the advances in antiretrovirals the last thirteen years since the FDA approved AZT. She describes the changed treatment paradigm as having gone from ‘treatment nihilism to that of cautious optimism’.

She reported that fortunately this has led to a dramatic reduction in HIV related mortality and morbidity. However multi-drug resistance to all classes of drugs has also been reported. Therapeutic failure can be associated with many factors as outlined previously, and currently there is an increasing interest in the role of TDM in optimising the clinical benefit of antiretroviral therapy as opposed to merely a ‘hope-based strategy’.

Dr Hoetelmans’ presentation focused on the achievements of TDM in the management of HIV to date – he also pointed out that ‘In the UK you have a good service to TDM’. In reality though ‘Only about 20% of physicians who were told that their patients had sub-optimal levels did anything about it.

Pharmacokinetic issues in children

In the course of her presentation, Dr Merry stated that ‘If there’s a good indication for TDM it’s in paediatric patients but in Liverpool this only represents about 3.5% of requests.’

Dr Courtney Fletcher gave an overview of the many challenges in treating paediatric HIV [10]. In particular he emphasised the importance of:

Recognition that children are not ‘small adults’ but are pharmacokinetically and perhaps pharmacodynamically distinct
An understanding that dose recommendations for the ‘average’ child ignore maturational changes in PK behaviour and variability
Whether administering the drug on a body weight or body surface area basis can lead to differences in the dose that may be clinically significant
The development of paediatric formulations

He reported very favourable outcomes however from the PACTG study 382, which is investigating a concentration-guided dosing regimen as a strategy to minimise potential sub-optimal drug levels. In this study of a NFV and EFV containing regimen designed to reach selected target concentrations, in an intent to treat analysis 75.5% of children had viral loads of <400 copies/ml (63% <50 copies/ml) after 48 weeks.

Although self-described as ‘cautious and conservative he explained that, ‘In the context of HIV-infected children, because of growth and development, I would favour using measured concentrations to guide dosing. I would not call it TDM, because TDM classically would imply that we know the therapeutic range for a given drug. We could, however, use concentrations to guide dosing using, the concentrations that the average adult would have, taking the standard dose of a drug as a target.’

Conclusion

This meeting provided an excellent overview of pharmacology in addition to an opportunity to look at the clinical discuss relevant case histories. We hope it becomes an annual fixture.

References:

All references refer to Clinical Pharmacology of Antiretroviral Therapy, Liverpool UK , March 29th/30th 2001.

Back D. Pharmacokinetic Principles
Postelnick M. Antimicrobial Pharmacokinetics-Pharmacodynamics
Palella F. HIV Outpatients Study
Miller V. Resistance Testing
Pirmohamed M. Adverse Drug Reactions
Gerber J. Drug interactions
Khoo S. Pharmacological Aspects of Treatment Failure
Merry C and Hoetelmans R. Therapeutic Drug Monitoring Principles and Practice
Merry C and Hoetelmans R. Therapeutic Drug Monitoring Principles and Practice
Fletcher C. Pharmacokinetic issues in children