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NEW MICROBIOLOGICA, 30, 346-349, 2007
Pharmacokinetics and pharmacodynamics
in HAART and antibiotic therapy
Marta Boffito
St. Stephen’s Centre, Chelsea and Westminster Hospital, London, UK Therapeutic agents used to inhibit the HIV replication are used in combination. The achievement of effective plas-ma concentrations of the drug in its active form, and sustaining such concentrations for the duration of a dosinginterval without exceeding thresholds of toxicity is fundamental in HIV therapy. The issues determining the absorp-tion, biotransformation, distribution to and activity at the intended site, and elimination, are myriad and complex.
Studies at molecular, cell, and tissue levels are useful for predicting the possible fate of these agents in vivo, butthe wide inter individual variability shown in whole-body pharmacokinetic studies is illustrative of the difficultyin making general statements rather than more guarded recommendations.
KEY WORDS: Antiretroviral drugs, Drug interactions, Pharmacology, HIV infection INTRODUCTION
inhibitors (NRTIs) are the current backbone ofvirtually all HAART combinations. NRTIs are pro- The long-term success of highly active anti- drugs because the active moiety is the triphos- retroviral therapy (HAART) depends on main- phate anabolite that is formed intracellularly.
taining concentrations of active drug at the site NRTI-triphosphates elicit their anti-HIV effect via of HIV replication sufficient to suppress viral repli- the inhibition of HIV reverse transcriptase, and cation and prevent the development of resistance.
presumably toxicity via the inhibition of mito- Although plasma concentrations of non-nucleo- chondrial DNA polymerase gamma. Therefore, side reverse transcriptase inhibitors (NNRTIs) and the use of these compounds depends upon a protease inhibitors (PI) have been correlated with quantitative understanding of the clinical phar- virological outcome, there are persistent questions macology of intracellular NRTI-triphosphates on the use of drug plasma concentration moni- toring to guide treatment. Theoretically, the high- Further, therapeutic drug monitoring is available er the trough concentration (measured at the end only for NNRTIs and PIs. Before this test can be of the dosing interval), the better the inhibition widely applied to routine antiretroviral therapy of HIV (Boffito et al., 2005).
management, large scale clinical trials should ide- However, precise therapeutic concentration ally be completed to demonstrate its utility.
ranges have not been identified for all anti- However, this presents a considerable challenge retroviral drugs. Nucleoside reverse transcriptase and at the moment there are a series of clinicalscenarios, such as hepatic impairment, in chil- dren, in women or in particular ethnic groups and during pregnancy, where therapeutic drug mon- itoring may be considered (Gazzard et al., 2006).
Importantly, drug concentrations alone are not Chelsea and Westminster HospitalLondon, UK the ultimate determinant of treatment outcome; other important factors include tolerability, Pharmacokinetics and pharmacodynamics in HAART and antibiotic therapy safety, adherence, treatment history, and resist- tatin activity (which includes the sum of ator- vastatin and two of its active metabolites)increased by 79%. By contrast, pravastatinexposure declined by 50%. These data are of DRUG-DRUG INTERACTIONS
utmost clinical importance since all statins havethe capacity for severe toxicity, including rhab- Clinically relevant antiretroviral drug-drug inter- actions may occur among antiretroviral drugsbelonging to the same or to different classes or Drug-drug interactions involving efavirenz between antiretroviral drugs and drugs received Metabolism induction by efavirenz may decrease by HIV positive patients for the treatment of co- PI exposure and therefore higher PI and/or riton- existing medical conditions, the treatment and pre- vention of opportunistic infections, for support- In fact, the recommended dose of lopinavir/riton- ive care or for the limitation of adverse events avir with efavirenz was 533/133 mg twice daily caused by antiretroviral agents (Boffito et al., 2005).
(addition of one capsule). Data on the dose of It is worth noting that despite the well known the new lopinavir/ritonavir formulation (tablet) mechanisms behind drug interactions involving that must be administered in the presence of NNRTIs and PIs (i.e. metabolism by cytochrome efavirenz are unclear and further studies are P450, CYP450, isoenzymes in the gastrointesti- needed (Kaletra 2006). The dosage regimen of nal tract and liver), other potential mechanisms boosted twice daily fosamprenavir/ritonavir involving such interactions are emerging (i.e.
(700/100 mg) does not require modification with transporters, gastric pH-dependent absorption).
efavirenz while the addition of 100 mg twice daily Examples of important drug-drug interactions of ritonavir is recommended if fosamprenavir is used once daily (Lexiva 2006).
The effect of efavirenz on the pharmacokinetics of pravastatin, atorvastatin and simvastatin in Metabolic disturbances associated with HIV HIV negative volunteers has also been studied infection and HAART are common. How best to and appeared to be safe (Fichtenbaum et al., treat these events is a pharmacological challenge 2002). From a pharmacokinetic perspective, because of the potential for clinically relevant efavirenz is a potent inducer of simvastatin drug-drug interactions associated with lipid low- metabolism (leading to a 60% decrease in its plas- ma concentrations) and a less potent, but still inhibitors, also known as statins, and antiretro- significant, inducer of atorvastatin metabolism viral agents (Fichtenbaum et al., 2002).
(35% decrease in exposure). Non-steady-state The primary route of metabolism for most statins exposure of efavirenz did not change, this needs is via oxidation utilizing the CYP450 3A4 path- to be confirmed by steady-state data. Higher way. Pravastatin, fluvastatin and rosuvastatin are doses should be considered for simvastatin when exceptions since they follow different metabol- ic/elimination pathways. The lactone drugs, like It has been reported that efavirenz and nevirap- lovastatin and simvastatin, which are adminis- tered as pro-drugs, are avid substrates for methadone (Neuman et al., 2006) and that tai- CYP3A4 and as such are inhibited by CYP3A4 loring the appropriate methadone coverage in inhibitors, which include the PIs and especial- efavirenz recipients can be problematic for the ly ritonavir (Fichtenbaum et al., 2002).
first few weeks of therapy. This has been recent- Drug interaction studies have been performed ly confirmed in presence of the NRTI abacavir with PIs and statins (Fichtenbaum et al., 2002).
(also responsible for an accelerated methadone Co-administration of saquinavir/ritonavir to clearance), where the marked reduction in HIV negative volunteers resulted in increased methadone concentrations was compensated by exposure to the active form of simvastatin by a methadone dose increase of approximately 30%, up to 60 weeks following antiretroviral initiation increased by 343%, although the total atorvas- Protease inhibitors and gastric acid reducing ciation with 40 mg of omeprazole. Addition of 100 mg of atazanavir or eight ounces of cola Chemical factors can affect drug absorption by influencing the state of the drug in the gas- omeprazole on atazanavir absorption.
trointestinal tract. The absorption of PIs is like- Co-administration of high dose ranitidine (300 ly to be decreased in the absence of gastric acid- ity. Therefore, interactions between PIs and anti- decrease amprenavir AUC by 30% while the Cmin acid drugs are theoretically possible.
was unchanged, suggesting a lack of effect of the This is important since a prevalence of 49.8% of higher gastric pH on trough concentrations.
nausea/anorexia/upper gastrointestinal symptoms These data, however, was not confirmed by a mul- has been reported by a large national cohort tiple dose study investigating the interaction study (Mathews et al., 2000), and confirmed by between esomeprazole, a potent proton pump a recent report investigating gastrointestinal acid- inhibitor, and fosamprenavir (with and without ity in HIV-infected subjects (Luber et al., 2004).
ritonavir), where amprenavir plasma exposure This suggests the frequent use of drugs able to was unchanged in the presence of esomeprazole control these symptoms, including anti-acidic drugs (H antagonists, acid neutralizers and phos- More studies are needed to confirm which PIs phate binders, proton pump inhibitors).
can be administered in presence of an altered gas- Available data suggest that there may be profound tric pH and how this may impact plasma con- differences across PIs in terms of absorption centrations and therefore virological response.
dependence on gastric pH and, therefore, in It has been argued that ritonavir boosting may terms of the influence that anti-acidic drugs may not be capable of counterbalancing the effect of anti acidic drugs on PI availability. Therefore, this Atazanavir and indinavir have been shown to option should be thoroughly investigated as well.
exhibit significantly decreased absorption whengiven with anti-acid drugs. The area under thecurve (AUC) and minimum concentration (C CONCLUSIONS
of atazanavir (400 mg once daily) was reducedby 84 and 87% when administered with buffered The pharmacology of the different classes of anti- didanosine (a didanosine formulation with retroviral agents is quite complex. Despite the cation chelating agents similar to Maalox) while expanded knowledge on the role of the hepatic the AUC of fosamprenavir (1400 twice daily) was CYP450 isoenzyme system in drug interactions, reduced by only 18%, with no significant effect drug interactions are often unpredictable.
Several different mechanisms can be responsi- Maalox. The deleterious effect of buffered drugs ble for interactions involving antiretrovirals, and on atazanavir absorption may be counterbal- these are complex and generally unclear.
anced by administering atazanavir two hours Consequently, therapeutic drug monitoring before or one hour after administration of these could be considered in this setting to confirm that drugs, while for H receptor antagonists (rani- adequate (not too low or too high and therefore tidine) the two drugs should be administered as subtherapeutic or toxic) plasma concentrations far apart as possible, e.g. 12 hours. Conversely, are being achieved. There are numerous data- given the prolonged effect of the proton pump bases that list all specific drug interactions that inhibitors and major decrease in atazanavir con- have been observed in HIV clinical practice and centrations with these drugs, this interaction can- that scientists believe may be likely.
not be managed by separating atazanavir and theproton pump inhibitor doses.
In fact, a recent warning issued by the manu- REFERENCES
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