{"id":8132,"date":"2002-09-11T20:35:46","date_gmt":"2002-09-11T20:35:46","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=8132"},"modified":"2002-09-11T20:35:46","modified_gmt":"2002-09-11T20:35:46","slug":"pharmacokinetics-and-further-benefits-of-therapeutic-drug-monitoring-tdm","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/8132","title":{"rendered":"Pharmacokinetics and further benefits of therapeutic drug monitoring (TDM)"},"content":{"rendered":"

Simon Collins, HIV i-Base<\/strong><\/p>\n

TDM to individualise indinavir\/ritonavir dosing<\/h2>\n

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. [1]<\/p>\n

Forty-two patients were treatment na\u00efve 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%).<\/p>\n

After a mean 13 months (\u00b1 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 na\u00efve 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.<\/p>\n

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.<\/p>\n

Food interaction with indinavir\/ritonavir<\/h2>\n

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. [2] 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.<\/p>\n

TDM for amprenavir\/ritonavir<\/h2>\n

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. [3] 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.<\/p>\n

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.<\/p>\n

TDM for lopinavir\/r and amprenavir (and NNRTIs)<\/h2>\n

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. [5]<\/p>\n

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).<\/p>\n\n\n\n\n\n\n\n\n\n\n\n
APV\u00a0concentrations (ng\/ml)<\/strong><\/td>\n<\/tr>\n
Regimen<\/td>\nN<\/td>\nMedian<\/td>\nRange<\/td>\n<\/tr>\n
APV600\/RTV100<\/td>\n9<\/td>\n1880<\/td>\n908-36<\/td>\n<\/tr>\n
APV 750\/LPV400\/RTV100<\/td>\n15<\/td>\n1113<\/td>\n510-2816<\/td>\n<\/tr>\n
APV 750\/LPV400\/APV*<\/td>\n6<\/td>\n678<\/td>\n528-2278<\/td>\n<\/tr>\n
LPV concentrations\u00a0(ng\/ml)<\/strong><\/td>\n<\/tr>\n
LPV 400\/RTV100<\/td>\n33<\/td>\n6295<\/td>\n1218-14452<\/td>\n<\/tr>\n
LPV 400\/RTV100\/APV*<\/td>\n12<\/td>\n2878<\/td>\n822-9327<\/td>\n<\/tr>\n
LPV 400\/RTV100+ NNRTI<\/td>\n8<\/td>\n4683<\/td>\n667-18892<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

* 600-1200mg BID<\/p>\n

The study concluded that is a complex PK interaction and given the marked interpatient variability highlights the potential importance of concentration monitoring (TDM).<\/p>\n

TDM for newly reported interaction between lopinavir\/r and nevirapine<\/h2>\n

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). [4]<\/p>\n\n\n\n\n\n\n
\u00a0<\/td>\n
\nCmin <\/strong><\/td>\n		Cmax<\/strong><\/td>\nTmax<\/strong><\/td>\n<\/tr>\n
No NNRTI<\/td>\n5690\u00a0(1420-11200)<\/td>\n124000\u00a0(3920-17300)<\/td>\n3.5h\u00a0(1-12)<\/td>\n<\/tr>\n
EFV<\/td>\n7625\u00a0(2870-11200)<\/td>\n14100\u00a0(6990-17300)<\/td>\n3.5h (2-12)<\/td>\n<\/tr>\n
NVP<\/td>\n3330\u00a0(1420-5240)<\/td>\n8110\u00a0(12300-3920)<\/td>\nN\/p<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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.<\/p>\n

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.<\/p>\n

References:<\/p>\n

    \n
  1. 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.<\/li>\n
  2. R Aarnoutse, J Wasmuth, G F\u00e4tkenheuer 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.<\/li>\n
  3. 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.<\/li>\n
  4. 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.<\/li>\n
  5. 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.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    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 …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-8132","post","type-post","status-publish","format-standard","hentry","category-antiretrovirals"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/8132","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=8132"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/8132\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=8132"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=8132"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=8132"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}